From 2f77a75d6215964552199b5b982e66f16b308a35 Mon Sep 17 00:00:00 2001 From: Manuel Holtgrewe Date: Thu, 5 Oct 2023 09:30:11 +0200 Subject: [PATCH] feat: implement parsing of clinvar-data-jsonl data (#198) --- src/common.rs | 10 +- src/db/to_bin/cli.rs | 62 ++- src/db/to_bin/clinvar/input.rs | 429 ++++++++++++------ src/db/to_bin/clinvar/mod.rs | 186 ++++++-- ...test__run_convert_jsonl_to_protobuf-2.snap | 293 ++++++++++++ ...__test__run_convert_jsonl_to_protobuf.snap | 269 +++++++++++ src/db/to_bin/vardbs/mod.rs | 2 +- src/proto/varfish/v1/clinvar.proto | 6 +- src/sv/query/clinvar.rs | 6 +- src/sv/query/mod.rs | 10 +- .../vardbs/clinvar/clinvar-svs.jsonl | 105 +++++ .../vardbs/clinvar/clinvar-svs.jsonl.gz | Bin 0 -> 137550 bytes .../vardbs/grch37/strucvar/clinvar.bed.gz | Bin 123820 -> 0 bytes .../vardbs/grch37/strucvar/clinvar.bed.gz.md5 | 1 - .../vardbs/grch37/strucvar/clinvar.bed.gz.tbi | Bin 519 -> 0 bytes .../grch37/strucvar/clinvar.bed.gz.tbi.md5 | 1 - .../vardbs/grch37/strucvar/clinvar.spec.json | 23 - 17 files changed, 1188 insertions(+), 215 deletions(-) create mode 100644 src/db/to_bin/clinvar/snapshots/varfish_server_worker__db__to_bin__clinvar__test__run_convert_jsonl_to_protobuf-2.snap create mode 100644 src/db/to_bin/clinvar/snapshots/varfish_server_worker__db__to_bin__clinvar__test__run_convert_jsonl_to_protobuf.snap create mode 100644 tests/db/to-bin/varfish-db-downloader/vardbs/clinvar/clinvar-svs.jsonl create mode 100644 tests/db/to-bin/varfish-db-downloader/vardbs/clinvar/clinvar-svs.jsonl.gz delete mode 100644 tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/clinvar.bed.gz delete mode 100644 tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/clinvar.bed.gz.md5 delete mode 100644 tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/clinvar.bed.gz.tbi delete mode 100644 tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/clinvar.bed.gz.tbi.md5 delete mode 100644 tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/clinvar.spec.json diff --git a/src/common.rs b/src/common.rs index f2d1652e..33dea389 100644 --- a/src/common.rs +++ b/src/common.rs @@ -2,7 +2,7 @@ use std::{ fs::File, - io::{BufRead, BufReader, BufWriter, Read, Write}, + io::{BufRead, BufReader, BufWriter, Write}, ops::Range, path::Path, }; @@ -60,7 +60,7 @@ pub fn build_chrom_map() -> IndexMap { } /// Transparently open a file with gzip decoder. -pub fn open_read_maybe_gz

(path: P) -> Result, anyhow::Error> +pub fn open_read_maybe_gz

(path: P) -> Result, anyhow::Error> where P: AsRef, { @@ -69,11 +69,11 @@ where let file = File::open(path)?; let bufreader = BufReader::new(file); let decoder = MultiGzDecoder::new(bufreader); - Ok(Box::new(decoder)) + Ok(Box::new(BufReader::new(decoder))) } else { tracing::trace!("Opening {:?} as plain text for reading", path.as_ref()); - let file = File::open(path)?; - Ok(Box::new(file)) + let file = File::open(path).map(BufReader::new)?; + Ok(Box::new(BufReader::new(file))) } } diff --git a/src/db/to_bin/cli.rs b/src/db/to_bin/cli.rs index e6b74b86..2da6d59c 100644 --- a/src/db/to_bin/cli.rs +++ b/src/db/to_bin/cli.rs @@ -13,6 +13,36 @@ use crate::{ }, }; +/// Select the assembly +#[derive( + clap::ValueEnum, + Clone, + Copy, + Debug, + strum::Display, + PartialEq, + Eq, + enum_map::Enum, + PartialOrd, + Ord, + Hash, +)] +pub enum Assembly { + /// GRCh37 + Grch37, + /// GRCh38 + Grch38, +} + +impl From for crate::db::to_bin::clinvar::input::Assembly { + fn from(val: Assembly) -> Self { + match val { + Assembly::Grch37 => crate::db::to_bin::clinvar::input::Assembly::Grch37, + Assembly::Grch38 => crate::db::to_bin::clinvar::input::Assembly::Grch38, + } + } +} + /// Select input/conversion type. #[derive( clap::ValueEnum, @@ -56,6 +86,9 @@ pub enum InputType { #[derive(Parser, Debug)] #[command(about = "Convert to binary protobuf files", long_about = None)] pub struct Args { + /// Optionally the assembly (required for ClinvarSv) + #[arg(long, value_enum)] + pub assembly: Option, /// Input type to convert to binary. #[arg(long, value_enum)] pub input_type: InputType, @@ -77,7 +110,13 @@ pub fn run(common_args: &crate::common::Args, args: &Args) -> Result<(), anyhow: tracing::info!("Starting conversion..."); match args.input_type { - InputType::ClinvarSv => clinvar::convert_to_bin(&args.path_input, &args.path_output_bin)?, + InputType::ClinvarSv => { + let assembly = args + .assembly + .expect("assembly required for ClinvarSv conversion"); + let assembly: crate::db::to_bin::clinvar::input::Assembly = assembly.into(); + clinvar::convert_to_bin(&args.path_input, &args.path_output_bin, assembly)? + } InputType::StrucvarInhouse => vardbs::convert_to_bin( &args.path_input, &args.path_output_bin, @@ -128,16 +167,21 @@ mod test { use super::{Args, InputType}; - #[test] - fn run_clinvar_sv_smoke() -> Result<(), anyhow::Error> { + #[rstest::rstest] + #[case(crate::db::to_bin::cli::Assembly::Grch37)] + #[case(crate::db::to_bin::cli::Assembly::Grch38)] + fn run_clinvar_sv_smoke( + #[case] assembly: crate::db::to_bin::cli::Assembly, + ) -> Result<(), anyhow::Error> { let tmp_dir = temp_testdir::TempDir::default(); let common_args = common::Args { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: Some(assembly), input_type: InputType::ClinvarSv, path_input: String::from( - "tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/clinvar.bed.gz", + "tests/db/to-bin/varfish-db-downloader/vardbs/clinvar/clinvar-svs.jsonl.gz", ), path_output_bin: tmp_dir.join("clinvar.bin"), }; @@ -154,6 +198,7 @@ mod test { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: None, input_type: InputType::StrucvarInhouse, path_input: String::from( "tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/inhouse.tsv", @@ -173,6 +218,7 @@ mod test { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: None, input_type: InputType::StrucvarDbVar, path_input: String::from( "tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/dbvar.bed.gz", @@ -192,6 +238,7 @@ mod test { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: None, input_type: InputType::StrucvarDgv, path_input: String::from( "tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/dgv.bed.gz", @@ -211,6 +258,7 @@ mod test { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: None, input_type: InputType::StrucvarDgvGs, path_input: String::from( "tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/dgv_gs.bed.gz", @@ -230,6 +278,7 @@ mod test { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: None, input_type: InputType::StrucvarExacCnv, path_input: String::from( "tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/exac.bed.gz", @@ -249,6 +298,7 @@ mod test { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: None, input_type: InputType::StrucvarG1k, path_input: String::from( "tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/g1k.bed.gz", @@ -268,6 +318,7 @@ mod test { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: None, input_type: InputType::StrucvarGnomadSv, path_input: String::from( "tests/db/to-bin/varfish-db-downloader/vardbs/grch37/strucvar/gnomad_sv.bed.gz", @@ -287,6 +338,7 @@ mod test { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: None, input_type: InputType::GeneRegion, path_input: String::from( "tests/db/to-bin/varfish-db-downloader/features/grch37/gene_regions/refseq.bed.gz", @@ -306,6 +358,7 @@ mod test { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: None, input_type: InputType::MaskedRegion, path_input: String::from( "tests/db/to-bin/varfish-db-downloader/features/grch37/masked/repeat.bed.gz", @@ -325,6 +378,7 @@ mod test { verbose: Verbosity::new(0, 0), }; let args = Args { + assembly: None, input_type: InputType::Xlink, path_input: String::from("tests/db/to-bin/varfish-db-downloader/genes/xlink/hgnc.tsv"), path_output_bin: tmp_dir.join("xlink.bin"), diff --git a/src/db/to_bin/clinvar/input.rs b/src/db/to_bin/clinvar/input.rs index 9d7432b5..ed05d702 100644 --- a/src/db/to_bin/clinvar/input.rs +++ b/src/db/to_bin/clinvar/input.rs @@ -1,151 +1,316 @@ //! Module with code supporting the parsing. +//! +//! Note that not the full model is implemented, only the parts that are needed for the +//! conversion of the ClinVar structural variants. -use std::collections::HashMap; - -use crate::sv::query::schema::{Pathogenicity, VariationType}; -use serde::{de, Deserialize, Deserializer}; -use tracing::warn; - -lazy_static::lazy_static! { - static ref VARIATION_TYPE_LABELS: HashMap<&'static str, VariationType> = { - let mut m = HashMap::new(); - m.insert("Complex", VariationType::Complex); - m.insert("copy number gain", VariationType::Dup); - m.insert("copy number loss", VariationType::Del); - m.insert("Deletion", VariationType::Del); - m.insert("Duplication", VariationType::Dup); - m.insert("fusion", VariationType::Bnd); - m.insert("Indel", VariationType::Cnv); - m.insert("Insertion", VariationType::Ins); - m.insert("Inversion", VariationType::Inv); - m.insert("Microsatellite", VariationType::Microsatellite); - m.insert("Tandem duplication", VariationType::Dup); - m.insert("Translocation", VariationType::Bnd); - m - }; +use crate::sv::query::clinvar::pbs::{Pathogenicity, VariationType}; + +/// Accession of a ClinVar record. +#[derive(Debug, serde::Deserialize, serde::Serialize)] +pub struct ClinVarAccession { + /// Accession string of the record. + pub acc: String, + /// Version of the accession. + pub version: u32, } -impl VariationType { - pub fn from_label(label: &str) -> Result { - if let Some(result) = VARIATION_TYPE_LABELS.get(label) { - Ok(*result) - } else { - Err(anyhow::anyhow!("Invalid VariationType label: {}", label)) +/// The values of review status are used to build the 'star ratings' displayed on the +/// ClinVar public site. +/// +/// - 0 stars: a conflict or not classified by submitter +/// - 1 star: classified by single submitter +/// - 2 stars: classified by multiple submitters +/// - 3 stars: reviewed by expert panel +/// - 4 stars: reviewed by professional society +#[derive(Debug, serde::Deserialize, serde::Serialize)] +pub enum ReviewStatus { + /// no assertion provided + #[serde(alias = "no assertion provided")] + NoAssertionProvided, + /// no assertion criteria provided + #[serde(alias = "no assertion criteria provided")] + NoAssertionCriteriaProvided, + /// no assertion provided, single submitter + #[serde(alias = "criteria provided, single submitter")] + CriteriaProvidedSingleSubmitter, + /// no assertion provided, multiple submitters, no conflicts + #[serde(alias = "criteria provided, multiple submitters, no conflicts")] + CriteriaProvidedMultipleSubmittersNoConflicts, + /// no assertion provided, conflicting interpretations + #[serde(alias = "criteria provided, conflicting interpretations")] + CriteriaProvidedConflictingInterpretations, + /// reviewed by expert panel + #[serde(alias = "reviewed by expert panel")] + ReviewedByExpertPanel, + /// practice guideline + #[serde(alias = "practice guideline")] + PracticeGuideline, +} + +/// Description of the clinical significance of a variant. +#[derive(Debug, Clone, Copy, serde::Deserialize, serde::Serialize)] +pub enum ClinicalSignificanceDescription { + /// affects + #[serde(alias = "affects")] + Affects, + /// benign + #[serde(alias = "benign")] + Benign, + /// established risk allele + #[serde(alias = "established risk allele")] + EstablishedRiskAllele, + /// likely benign + #[serde(alias = "likely benign")] + LikelyBenign, + /// likely pathogenic + #[serde(alias = "likely pathogenic")] + LikelyPathogenic, + /// likely pathogenic, low penetrance + #[serde(alias = "likely pathogenic, low penetrance")] + LikelyPathogenicLowPenetrance, + /// likely risk allele + #[serde(alias = "likely risk allele")] + LikelyRiskAllele, + /// pathogenic + #[serde(alias = "pathogenic")] + Pathogenic, + /// pathogenic, low penetrance + #[serde(alias = "pathogenic, low penetrance")] + PathogenicLowPenetrance, + /// uncertain risk allele + #[serde(alias = "uncertain risk allele")] + UncertainRiskAllele, + /// uncertain significance + #[serde(alias = "uncertain significance")] + UncertainSignificance, + /// association + #[serde(alias = "association")] + Association, + /// association not found + #[serde(alias = "association not found")] + AssociationNotFound, + /// confers sensitivity + #[serde(alias = "confers sensitivity")] + ConfersSensitivity, + /// conflicting data from submitters + #[serde(alias = "conflicting data from submitters")] + ConflictingDataFromSubmitters, + /// drug response + #[serde(alias = "drug response")] + DrugResponse, + /// not provided + #[serde(alias = "not provided")] + NotProvided, + /// other + #[serde(alias = "other")] + Other, + /// protective + #[serde(alias = "protective")] + Protective, + /// risk factor + #[serde(alias = "risk factor")] + RiskFactory, +} + +impl TryInto for ClinicalSignificanceDescription { + type Error = anyhow::Error; + + fn try_into(self) -> Result { + match self { + ClinicalSignificanceDescription::LikelyBenign => Ok(Pathogenicity::Benign), + ClinicalSignificanceDescription::LikelyPathogenic + | ClinicalSignificanceDescription::LikelyPathogenicLowPenetrance => { + Ok(Pathogenicity::LikelyPathogenic) + } + ClinicalSignificanceDescription::Pathogenic + | ClinicalSignificanceDescription::PathogenicLowPenetrance => { + Ok(Pathogenicity::Pathogenic) + } + ClinicalSignificanceDescription::UncertainSignificance => Ok(Pathogenicity::Uncertain), + ClinicalSignificanceDescription::Benign + | ClinicalSignificanceDescription::Protective => Ok(Pathogenicity::Benign), + _ => anyhow::bail!("unsupported clinical significance: {:?}", self), } } } -lazy_static::lazy_static! { - static ref PATHOGENICITY_LABELS: HashMap<&'static str, Pathogenicity> = { - let mut m = HashMap::new(); - m.insert("{\"benign\"}", Pathogenicity::Benign); - m.insert("{\"benign\",\"likely benign\"}", Pathogenicity::LikelyBenign); - m.insert("{\"likely benign\"}", Pathogenicity::LikelyBenign); - m.insert("{\"likely pathogenic\"}", Pathogenicity::LikelyPathogenic); - m.insert("{\"likely pathogenic\",\"pathogenic\"}", Pathogenicity::LikelyPathogenic); - m.insert("{\"pathogenic\"}", Pathogenicity::Pathogenic); - m.insert("{\"uncertain significance\"}", Pathogenicity::Uncertain); - - m - }; +/// Description of the clinical significance of a variant. +#[derive(Debug, serde::Deserialize, serde::Serialize)] +pub struct ClinicalSignificance { + /// Review status of the variant. + pub review_status: ReviewStatus, + /// Description of the clinical significance of a variant. + pub description: ClinicalSignificanceDescription, +} + +/// Identifier of an assembly. +#[derive(Debug, Clone, PartialEq, Eq, Copy, serde::Deserialize, serde::Serialize)] +pub enum Assembly { + /// GRCh38 + #[serde(alias = "GRCh38")] + Grch38, + /// GRCh37 + #[serde(alias = "GRCh37")] + Grch37, + /// NCBI36 + #[serde(alias = "NCBI36")] + Ncib36, } -impl Pathogenicity { - pub fn from_label(label: &str) -> Result { - if let Some(pathogenicity) = PATHOGENICITY_LABELS.get(label) { - Ok(*pathogenicity) - } else { - warn!("Cannot decode pathogenicity from {}", label); - Ok(Pathogenicity::Uncertain) +/// Description of a location on a sequence. +#[derive(Debug, serde::Deserialize, serde::Serialize)] +pub struct SequenceLocation { + /// Assembly of the location + pub assembly: Assembly, + /// Chromosome + pub chr: String, + /// Accession of the chromosome + pub accession: Option, + /// Start position + pub start: Option, + /// Stop position, + pub stop: Option, + /// Inner start position + pub inner_start: Option, + /// Inner stop position + pub inner_stop: Option, + /// Outer start position + pub outer_start: Option, + /// Outer stop position + pub outer_stop: Option, + /// Variant length + pub variant_length: Option, + /// Position in VCF format + pub position_vcf: Option, + /// Reference allele in VCF format + pub reference_allele_vcf: Option, + /// Alternate allele in VCF format + pub alternate_allele_vcf: Option, +} + +#[derive(Debug, Clone, Copy, serde::Deserialize, serde::Serialize)] +pub enum MeasureType { + /// Gene + #[serde(alias = "gene")] + Gene, + /// Variation + #[serde(alias = "variation")] + Variation, + /// Insertion + #[serde(alias = "insertion")] + Insertion, + /// Deletion + #[serde(alias = "deletion")] + Deletion, + /// Single nucleotide variant + #[serde(alias = "single nucleotide variant")] + SingleNucleotideVariant, + /// Indel + #[serde(alias = "indel")] + Indel, + /// Duplication + #[serde(alias = "duplication")] + Duplication, + /// Tandem duplication + #[serde(alias = "tandem duplication")] + TandemDuplication, + /// Structural variant + #[serde(alias = "structural variant")] + StructuralVariant, + /// Copy number gain + #[serde(alias = "copy number gain")] + CopyNumberGain, + /// Copy number loss + #[serde(alias = "copy number loss")] + CopyNumberLoss, + /// Protein change only + #[serde(alias = "protein only")] + ProteinOnly, + /// Microsatellite + #[serde(alias = "microsatellite")] + Microsatellite, + // Fusion + #[serde(alias = "fusion")] + Fusion, + /// Inversion + #[serde(alias = "inversion")] + Inversion, + /// Translocation + #[serde(alias = "translocation")] + Translocation, + /// QTL + #[serde(alias = "qtl")] + Qtl, + /// Complex variant + #[serde(alias = "complex")] + Complex, + /// Other variant + #[serde(alias = "other")] + Other, +} + +impl TryInto for MeasureType { + type Error = anyhow::Error; + + fn try_into(self) -> Result { + match self { + MeasureType::Deletion => Ok(VariationType::Del), + MeasureType::Duplication => Ok(VariationType::Dup), + MeasureType::TandemDuplication => Ok(VariationType::Dup), + MeasureType::StructuralVariant => todo!(), + MeasureType::CopyNumberGain => Ok(VariationType::Dup), + MeasureType::CopyNumberLoss => Ok(VariationType::Del), + MeasureType::Microsatellite => Ok(VariationType::Microsatellite), + MeasureType::Inversion => Ok(VariationType::Inv), + MeasureType::Translocation => Ok(VariationType::Bnd), + MeasureType::Complex => Ok(VariationType::Complex), + MeasureType::SingleNucleotideVariant + | MeasureType::Gene + | MeasureType::Variation + | MeasureType::Insertion + | MeasureType::Indel + | MeasureType::ProteinOnly + | MeasureType::Fusion + | MeasureType::Qtl + | MeasureType::Other => anyhow::bail!("unsupported measure type: {:?}", self), } } } -/// Record as created by VarFish DB Downloader. -#[derive(Debug, Deserialize)] -pub struct Record { - /// Chromosome name - pub chromosome: String, - /// 1-based start position - pub begin: i32, - /// 1-based end position - pub end: i32, - /// unused - #[allow(dead_code)] - bin: u32, - /// unused - #[allow(dead_code)] - reference: String, - /// unused - #[allow(dead_code)] - alternative: String, - /// unused - #[allow(dead_code)] - clinvar_version: String, - /// unused - #[allow(dead_code)] - set_type: String, - /// ClinVar SV variation type - #[serde(deserialize_with = "from_variation_type_label")] - pub variation_type: VariationType, - /// unused - #[allow(dead_code)] - symbols: String, - /// unused - #[allow(dead_code)] - hgnc_ids: String, - /// The ClinVar VCV identifier - pub vcv: String, - /// unused - #[allow(dead_code)] - summary_clinvar_review_status_label: String, - /// unused - #[allow(dead_code)] - summary_clinvar_pathogenicity_label: String, - /// Pathogenicity - #[serde( - alias = "summary_clinvar_pathogenicity", - deserialize_with = "from_pathogenicity_summary" - )] - pub pathogenicity: Pathogenicity, - /// unused - #[allow(dead_code)] - summary_clinvar_gold_stars: String, - /// unused - #[allow(dead_code)] - summary_paranoid_review_status_label: String, - /// unused - #[allow(dead_code)] - summary_paranoid_pathogenicity_label: String, - /// unused - #[allow(dead_code)] - summary_paranoid_pathogenicity: String, - /// unused - #[allow(dead_code)] - summary_paranoid_gold_stars: String, - /// unused - #[allow(dead_code)] - details: String, +/// A single measure / variant. +#[derive(Debug, serde::Deserialize, serde::Serialize)] +pub struct Measure { + /// Type of the measure. + pub r#type: MeasureType, + /// Locations in the sequence, for each assembly. + pub sequence_locations: Vec, } -/// Deserialize "VariationType" from ClinVar TSV file -/// -/// This function will strip everything after the first underscore. -fn from_variation_type_label<'de, D>(deserializer: D) -> Result -where - D: Deserializer<'de>, -{ - let s: &str = Deserialize::deserialize(deserializer)?; - VariationType::from_label(s).map_err(de::Error::custom) +/// A set of measures / variants. +#[derive(Debug, serde::Deserialize, serde::Serialize)] +pub struct MeasureSet { + /// Accession of the record. + pub acc: String, + /// Version of the accession. + pub version: u32, + /// Measures / variants. + pub measures: Vec, } -/// Deserialize "Pathogenicity" from ClinVar TSV file -/// -/// This function will strip everything after the first underscore. -fn from_pathogenicity_summary<'de, D>(deserializer: D) -> Result -where - D: Deserializer<'de>, -{ - let s: &str = Deserialize::deserialize(deserializer)?; - Pathogenicity::from_label(s).map_err(de::Error::custom) +/// A reference ClinVar assertion. +#[derive(Debug, serde::Deserialize, serde::Serialize)] +pub struct ReferenceClinVarAssertion { + /// The ClinVar accession + pub clinvar_accession: ClinVarAccession, + /// The ClinVar significance + pub clinical_significance: ClinicalSignificance, + /// The ClinVar measure set + pub measures: MeasureSet, +} + +/// A ClinVar set. +#[derive(Debug, serde::Deserialize, serde::Serialize)] +pub struct ClinVarSet { + /// The reference ClinVar accession + pub reference_clinvar_assertion: ReferenceClinVarAssertion, } diff --git a/src/db/to_bin/clinvar/mod.rs b/src/db/to_bin/clinvar/mod.rs index e4bbc973..a93cd070 100644 --- a/src/db/to_bin/clinvar/mod.rs +++ b/src/db/to_bin/clinvar/mod.rs @@ -1,71 +1,163 @@ //! Code for converting ClinVar database to binary. -use std::{fs::File, io::Write, path::Path, time::Instant}; +use std::{fs::File, io::BufRead, io::Write, path::Path, time::Instant}; use prost::Message; use thousands::Separable; use crate::{ common::{build_chrom_map, open_read_maybe_gz, trace_rss_now}, - sv::query::clinvar::pbs::{SvDatabase, SvRecord}, + sv::query::clinvar::pbs::{Pathogenicity, SvDatabase, SvRecord}, }; -mod input; +pub mod input; -/// Helper to convert VCV IDs to numbers. -fn numeric_vcv_id(raw_id: &str) -> Result { +/// Helper to convert RCV IDs to numbers. +fn numeric_rcv_id(raw_id: &str) -> Result { let clean_id: String = raw_id .chars() - .skip("VCV".len()) + .skip("RCV".len()) .skip_while(|c| *c == '0') .collect(); clean_id .parse::() - .map_err(|e| anyhow::anyhow!("could not parse VCV id {:?}: {}", &clean_id, &e)) + .map_err(|e| anyhow::anyhow!("could not parse RCV id {:?}: {}", &clean_id, &e)) } -/// Perform conversion to protocolbuffers `.bin` file. -pub fn convert_to_bin(path_input_tsv: P, path_output_bin: Q) -> Result<(), anyhow::Error> -where - P: AsRef, - Q: AsRef, -{ +/// Read JSONL file and convert to protobuf records. +fn convert_jsonl_to_protobuf( + reader: Box, + assembly: input::Assembly, +) -> Result, anyhow::Error> { let chrom_map = build_chrom_map(); - let mut reader = csv::ReaderBuilder::new() - .comment(Some(b'#')) - .delimiter(b'\t') - .has_headers(false) - .from_reader(open_read_maybe_gz(path_input_tsv)?); - let before_parsing = Instant::now(); - let mut records = Vec::new(); - for record in reader.deserialize() { - match record { + for line in reader.lines() { + // get next line into a String + let line = if let Ok(line) = line { + line + } else { + anyhow::bail!("error reading line from input file") + }; + + // deserialize JSONL record from line + let record = serde_json::from_str(&line); + let record = match record { Err(e) => { - tracing::warn!("error parsing ClinVar record: {}", e); + tracing::warn!("error deserializing JSONL record: \"{}\" in {}", e, &line); + continue; } Ok(record) => { - let record: input::Record = record; - let variation_type: crate::sv::query::clinvar::pbs::VariationType = - record.variation_type.into(); - let pathogenicity: crate::sv::query::clinvar::pbs::Pathogenicity = - record.pathogenicity.into(); - if let Some(chrom_no) = chrom_map.get(&record.chromosome) { + let record: input::ClinVarSet = record; + record + } + }; + + let rcv = numeric_rcv_id(&record.reference_clinvar_assertion.clinvar_accession.acc)?; + + // convert from JSONL to protocolbuffers: pathogenicity + let pathogenicity: Result = record + .reference_clinvar_assertion + .clinical_significance + .description + .try_into(); + let pathogenicity = if let Ok(pathogenicity) = pathogenicity { + pathogenicity as i32 + } else { + continue; + }; + + // there can be multiple measures, we consider them all + for measure in &record.reference_clinvar_assertion.measures.measures { + // convert from JSONL to protocolbuffers: variation type + let variation_type: Result< + crate::sv::query::clinvar::pbs::VariationType, + anyhow::Error, + > = measure.r#type.try_into(); + let variation_type = if let Ok(variation_type) = variation_type { + variation_type as i32 + } else { + continue; + }; + + // we process sequence locations on the selected assembly + for sl in &measure.sequence_locations { + if sl.assembly != assembly { + continue; + } + let chrom_no = if let Some(chrom_no) = chrom_map.get(&sl.chr) { + *chrom_no as i32 + } else { + tracing::warn!("unknown chromosome {}", &sl.chr); + continue; + }; + + if let (Some(start), Some(stop)) = (sl.start, sl.stop) { records.push(SvRecord { - chrom_no: *chrom_no as i32, - start: record.begin + 1, - stop: record.end, - variation_type: variation_type as i32, - pathogenicity: pathogenicity as i32, - vcv: numeric_vcv_id(&record.vcv)?, + chrom_no, + start, + stop, + variation_type, + pathogenicity, + rcv, + }); + } else if let (Some(inner_start), Some(inner_stop)) = + (sl.inner_start, sl.inner_stop) + { + records.push(SvRecord { + chrom_no, + start: inner_start, + stop: inner_stop, + variation_type, + pathogenicity, + rcv, + }); + } else if let (Some(outer_start), Some(outer_stop)) = + (sl.outer_start, sl.outer_stop) + { + records.push(SvRecord { + chrom_no, + start: outer_start, + stop: outer_stop, + variation_type, + pathogenicity, + rcv, + }); + } else if let (Some(position_vcf), Some(reference_allele_vcf), Some(_)) = ( + sl.position_vcf, + sl.reference_allele_vcf.as_ref(), + sl.alternate_allele_vcf.as_ref(), + ) { + records.push(SvRecord { + chrom_no, + start: position_vcf + 1, + stop: position_vcf + reference_allele_vcf.len() as i32, + variation_type, + pathogenicity, + rcv, }); - } else { - tracing::warn!("unknown chromosome {}", &record.chromosome); } } } } + Ok(records) +} + +/// Perform conversion to protocolbuffers `.bin` file. +pub fn convert_to_bin( + path_input_jsonl: P, + path_output_bin: Q, + assembly: input::Assembly, +) -> Result<(), anyhow::Error> +where + P: AsRef, + Q: AsRef, +{ + let reader = open_read_maybe_gz(path_input_jsonl)?; + let before_parsing = Instant::now(); + + let records = convert_jsonl_to_protobuf(reader, assembly)?; + let clinvar_db = SvDatabase { records }; tracing::debug!( @@ -87,3 +179,23 @@ where Ok(()) } + +#[cfg(test)] +mod test { + use crate::common::open_read_maybe_gz; + use crate::db::to_bin::clinvar::input::Assembly; + + #[rstest::rstest] + #[case(Assembly::Grch37)] + #[case(Assembly::Grch38)] + fn run_convert_jsonl_to_protobuf(#[case] assembly: Assembly) -> Result<(), anyhow::Error> { + let reader = open_read_maybe_gz( + "tests/db/to-bin/varfish-db-downloader/vardbs/clinvar/clinvar-svs.jsonl", + )?; + let records = super::convert_jsonl_to_protobuf(reader, assembly)?; + + insta::assert_yaml_snapshot!(records); + + Ok(()) + } +} diff --git a/src/db/to_bin/clinvar/snapshots/varfish_server_worker__db__to_bin__clinvar__test__run_convert_jsonl_to_protobuf-2.snap b/src/db/to_bin/clinvar/snapshots/varfish_server_worker__db__to_bin__clinvar__test__run_convert_jsonl_to_protobuf-2.snap new file mode 100644 index 00000000..0293635e --- /dev/null +++ b/src/db/to_bin/clinvar/snapshots/varfish_server_worker__db__to_bin__clinvar__test__run_convert_jsonl_to_protobuf-2.snap @@ -0,0 +1,293 @@ +--- +source: src/db/to_bin/clinvar/mod.rs +expression: records +--- +- chrom_no: 6 + start: 101528 + stop: 227833 + variation_type: 2 + pathogenicity: 0 + rcv: 50292 +- chrom_no: 0 + start: 147228867 + stop: 147248577 + variation_type: 2 + pathogenicity: 2 + rcv: 50299 +- chrom_no: 6 + start: 70356011 + stop: 70537428 + variation_type: 2 + pathogenicity: 2 + rcv: 50317 +- chrom_no: 6 + start: 10649696 + stop: 11329787 + variation_type: 2 + pathogenicity: 2 + rcv: 50319 +- chrom_no: 20 + start: 35734654 + stop: 35879759 + variation_type: 2 + pathogenicity: 2 + rcv: 50337 +- chrom_no: 0 + start: 149041013 + stop: 149699420 + variation_type: 2 + pathogenicity: 0 + rcv: 50339 +- chrom_no: 1 + start: 242930600 + stop: 243007359 + variation_type: 2 + pathogenicity: 0 + rcv: 50458 +- chrom_no: 5 + start: 259528 + stop: 307998 + variation_type: 2 + pathogenicity: 0 + rcv: 50474 +- chrom_no: 5 + start: 259528 + stop: 293493 + variation_type: 2 + pathogenicity: 0 + rcv: 50518 +- chrom_no: 2 + start: 2342852 + stop: 2796629 + variation_type: 2 + pathogenicity: 2 + rcv: 50588 +- chrom_no: 10 + start: 196966 + stop: 244236 + variation_type: 3 + pathogenicity: 2 + rcv: 50265 +- chrom_no: 0 + start: 148867551 + stop: 149699420 + variation_type: 3 + pathogenicity: 0 + rcv: 50266 +- chrom_no: 1 + start: 242930600 + stop: 243059659 + variation_type: 3 + pathogenicity: 0 + rcv: 50281 +- chrom_no: 22 + start: 155231256 + stop: 155251871 + variation_type: 3 + pathogenicity: 0 + rcv: 50305 +- chrom_no: 22 + start: 155231256 + stop: 155251871 + variation_type: 3 + pathogenicity: 0 + rcv: 50306 +- chrom_no: 0 + start: 149041013 + stop: 149699420 + variation_type: 3 + pathogenicity: 0 + rcv: 50340 +- chrom_no: 4 + start: 629455 + stop: 820475 + variation_type: 3 + pathogenicity: 0 + rcv: 50363 +- chrom_no: 11 + start: 61091958 + stop: 61921447 + variation_type: 3 + pathogenicity: 2 + rcv: 50369 +- chrom_no: 1 + start: 242930600 + stop: 243007359 + variation_type: 3 + pathogenicity: 0 + rcv: 50463 +- chrom_no: 5 + start: 259528 + stop: 307998 + variation_type: 3 + pathogenicity: 0 + rcv: 50482 +- chrom_no: 15 + start: 89817659 + stop: 89861760 + variation_type: 3 + pathogenicity: 4 + rcv: 3614 +- chrom_no: 7 + start: 53536328 + stop: 53598019 + variation_type: 3 + pathogenicity: 4 + rcv: 4182 +- chrom_no: 7 + start: 53537321 + stop: 53574220 + variation_type: 3 + pathogenicity: 4 + rcv: 4183 +- chrom_no: 16 + start: 3543558 + stop: 3543559 + variation_type: 1 + pathogenicity: 4 + rcv: 4692 +- chrom_no: 4 + start: 77436046 + stop: 77444215 + variation_type: 3 + pathogenicity: 4 + rcv: 6747 +- chrom_no: 8 + start: 139570503 + stop: 139571539 + variation_type: 3 + pathogenicity: 4 + rcv: 7011 +- chrom_no: 21 + start: 40742514 + stop: 40762546 + variation_type: 2 + pathogenicity: 2 + rcv: 536272 +- chrom_no: 22 + start: 69080668 + stop: 69177002 + variation_type: 2 + pathogenicity: 4 + rcv: 539041 +- chrom_no: 16 + start: 56769999 + stop: 56774226 + variation_type: 2 + pathogenicity: 2 + rcv: 554988 +- chrom_no: 22 + start: 68890034 + stop: 69177002 + variation_type: 2 + pathogenicity: 4 + rcv: 633513 +- chrom_no: 3 + start: 77116840 + stop: 77134716 + variation_type: 2 + pathogenicity: 2 + rcv: 638336 +- chrom_no: 1 + start: 233194517 + stop: 233198703 + variation_type: 2 + pathogenicity: 2 + rcv: 638545 +- chrom_no: 22 + start: 103031893 + stop: 103045546 + variation_type: 2 + pathogenicity: 4 + rcv: 640484 +- chrom_no: 1 + start: 32358735 + stop: 32358736 + variation_type: 2 + pathogenicity: 4 + rcv: 6031 +- chrom_no: 11 + start: 115120779 + stop: 115120779 + variation_type: 3 + pathogenicity: 4 + rcv: 8451 +- chrom_no: 11 + start: 114836472 + stop: 114836472 + variation_type: 3 + pathogenicity: 4 + rcv: 8460 +- chrom_no: 0 + start: 228345537 + stop: 228345537 + variation_type: 3 + pathogenicity: 3 + rcv: 256421 +- chrom_no: 13 + start: 21775989 + stop: 21776009 + variation_type: 3 + pathogenicity: 3 + rcv: 256440 +- chrom_no: 20 + start: 47545768 + stop: 47545769 + variation_type: 2 + pathogenicity: 3 + rcv: 256480 +- chrom_no: 17 + start: 43479513 + stop: 43479513 + variation_type: 3 + pathogenicity: 3 + rcv: 416351 +- chrom_no: 1 + start: 179454322 + stop: 179454323 + variation_type: 2 + pathogenicity: 2 + rcv: 256437 +- chrom_no: 16 + start: 12899881 + stop: 12899882 + variation_type: 2 + pathogenicity: 4 + rcv: 5360 +- chrom_no: 2 + start: 33100045 + stop: 33100046 + variation_type: 0 + pathogenicity: 3 + rcv: 1849900 +- chrom_no: 13 + start: 99641905 + stop: 99641906 + variation_type: 2 + pathogenicity: 2 + rcv: 2265366 +- chrom_no: 22 + start: 154156796 + stop: 154227925 + variation_type: 0 + pathogenicity: 3 + rcv: 852264 +- chrom_no: 14 + start: 38632006 + stop: 38632007 + variation_type: 2 + pathogenicity: 4 + rcv: 622432 +- chrom_no: 7 + start: 144900557 + stop: 144900557 + variation_type: 3 + pathogenicity: 4 + rcv: 622481 +- chrom_no: 0 + start: 1718780 + stop: 1718782 + variation_type: 3 + pathogenicity: 4 + rcv: 623933 + diff --git a/src/db/to_bin/clinvar/snapshots/varfish_server_worker__db__to_bin__clinvar__test__run_convert_jsonl_to_protobuf.snap b/src/db/to_bin/clinvar/snapshots/varfish_server_worker__db__to_bin__clinvar__test__run_convert_jsonl_to_protobuf.snap new file mode 100644 index 00000000..607b9160 --- /dev/null +++ b/src/db/to_bin/clinvar/snapshots/varfish_server_worker__db__to_bin__clinvar__test__run_convert_jsonl_to_protobuf.snap @@ -0,0 +1,269 @@ +--- +source: src/db/to_bin/clinvar/mod.rs +expression: records +--- +- chrom_no: 6 + start: 101528 + stop: 227833 + variation_type: 2 + pathogenicity: 0 + rcv: 50292 +- chrom_no: 0 + start: 147756734 + stop: 147776466 + variation_type: 2 + pathogenicity: 2 + rcv: 50299 +- chrom_no: 6 + start: 70891025 + stop: 71072442 + variation_type: 2 + pathogenicity: 2 + rcv: 50317 +- chrom_no: 6 + start: 10610069 + stop: 11290160 + variation_type: 2 + pathogenicity: 2 + rcv: 50319 +- chrom_no: 20 + start: 7743711 + stop: 7865746 + variation_type: 2 + pathogenicity: 2 + rcv: 50337 +- chrom_no: 1 + start: 241988449 + stop: 242065208 + variation_type: 2 + pathogenicity: 0 + rcv: 50458 +- chrom_no: 5 + start: 259528 + stop: 307998 + variation_type: 2 + pathogenicity: 0 + rcv: 50474 +- chrom_no: 5 + start: 259528 + stop: 293493 + variation_type: 2 + pathogenicity: 0 + rcv: 50518 +- chrom_no: 2 + start: 2301168 + stop: 2754945 + variation_type: 2 + pathogenicity: 2 + rcv: 50588 +- chrom_no: 10 + start: 196966 + stop: 244236 + variation_type: 3 + pathogenicity: 2 + rcv: 50265 +- chrom_no: 6 + start: 61006478 + stop: 62410831 + variation_type: 3 + pathogenicity: 0 + rcv: 50266 +- chrom_no: 1 + start: 241988449 + stop: 242126245 + variation_type: 3 + pathogenicity: 0 + rcv: 50281 +- chrom_no: 22 + start: 156001591 + stop: 156022206 + variation_type: 3 + pathogenicity: 0 + rcv: 50305 +- chrom_no: 22 + start: 156001591 + stop: 156022206 + variation_type: 3 + pathogenicity: 0 + rcv: 50306 +- chrom_no: 4 + start: 629340 + stop: 820360 + variation_type: 3 + pathogenicity: 0 + rcv: 50363 +- chrom_no: 11 + start: 60698177 + stop: 61527666 + variation_type: 3 + pathogenicity: 2 + rcv: 50369 +- chrom_no: 1 + start: 241988449 + stop: 242065208 + variation_type: 3 + pathogenicity: 0 + rcv: 50463 +- chrom_no: 5 + start: 259528 + stop: 307998 + variation_type: 3 + pathogenicity: 0 + rcv: 50482 +- chrom_no: 15 + start: 89751251 + stop: 89795352 + variation_type: 3 + pathogenicity: 4 + rcv: 3614 +- chrom_no: 7 + start: 52623768 + stop: 52685459 + variation_type: 3 + pathogenicity: 4 + rcv: 4182 +- chrom_no: 7 + start: 52624761 + stop: 52661660 + variation_type: 3 + pathogenicity: 4 + rcv: 4183 +- chrom_no: 8 + start: 32973498 + stop: 33001604 + variation_type: 3 + pathogenicity: 4 + rcv: 4682 +- chrom_no: 16 + start: 3640264 + stop: 3640265 + variation_type: 1 + pathogenicity: 4 + rcv: 4692 +- chrom_no: 4 + start: 78140222 + stop: 78148391 + variation_type: 3 + pathogenicity: 4 + rcv: 6747 +- chrom_no: 8 + start: 136676051 + stop: 136677087 + variation_type: 3 + pathogenicity: 4 + rcv: 7011 +- chrom_no: 16 + start: 58692638 + stop: 58696865 + variation_type: 2 + pathogenicity: 2 + rcv: 554988 +- chrom_no: 3 + start: 76195687 + stop: 76213563 + variation_type: 2 + pathogenicity: 2 + rcv: 638336 +- chrom_no: 1 + start: 232329807 + stop: 232333993 + variation_type: 2 + pathogenicity: 2 + rcv: 638545 +- chrom_no: 1 + start: 32133666 + stop: 32133667 + variation_type: 2 + pathogenicity: 4 + rcv: 6031 +- chrom_no: 11 + start: 114682974 + stop: 114682974 + variation_type: 3 + pathogenicity: 4 + rcv: 8451 +- chrom_no: 11 + start: 114398667 + stop: 114398667 + variation_type: 3 + pathogenicity: 4 + rcv: 8460 +- chrom_no: 0 + start: 228157836 + stop: 228157836 + variation_type: 3 + pathogenicity: 3 + rcv: 256421 +- chrom_no: 13 + start: 21307830 + stop: 21307850 + variation_type: 3 + pathogenicity: 3 + rcv: 256440 +- chrom_no: 20 + start: 46125854 + stop: 46125855 + variation_type: 2 + pathogenicity: 3 + rcv: 256480 +- chrom_no: 17 + start: 45899548 + stop: 45899548 + variation_type: 3 + pathogenicity: 3 + rcv: 416351 +- chrom_no: 1 + start: 178589595 + stop: 178589596 + variation_type: 2 + pathogenicity: 2 + rcv: 256437 +- chrom_no: 16 + start: 12996564 + stop: 12996565 + variation_type: 2 + pathogenicity: 4 + rcv: 5360 +- chrom_no: 13 + start: 99175568 + stop: 99175569 + variation_type: 2 + pathogenicity: 2 + rcv: 2265366 +- chrom_no: 14 + start: 38339805 + stop: 38339806 + variation_type: 2 + pathogenicity: 4 + rcv: 622432 +- chrom_no: 7 + start: 143818387 + stop: 143818387 + variation_type: 3 + pathogenicity: 4 + rcv: 622481 +- chrom_no: 0 + start: 1787341 + stop: 1787343 + variation_type: 3 + pathogenicity: 4 + rcv: 623933 +- chrom_no: 7 + start: 86652314 + stop: 86662912 + variation_type: 2 + pathogenicity: 4 + rcv: 498744 +- chrom_no: 9 + start: 129162520 + stop: 129249183 + variation_type: 4 + pathogenicity: 4 + rcv: 2468904 +- chrom_no: 6 + start: 102178523 + stop: 102225311 + variation_type: 4 + pathogenicity: 4 + rcv: 2468904 + diff --git a/src/db/to_bin/vardbs/mod.rs b/src/db/to_bin/vardbs/mod.rs index 267bb407..4239d6ab 100644 --- a/src/db/to_bin/vardbs/mod.rs +++ b/src/db/to_bin/vardbs/mod.rs @@ -32,7 +32,7 @@ pub enum InputFileType { } /// Deserialize from CSV reader to an `Option` fn deserialize_loop( - reader: &mut csv::Reader>, + reader: &mut csv::Reader>, ) -> Result, anyhow::Error> where Rec: TryInto> + for<'de> serde::Deserialize<'de>, diff --git a/src/proto/varfish/v1/clinvar.proto b/src/proto/varfish/v1/clinvar.proto index ccbf4e95..ae700885 100644 --- a/src/proto/varfish/v1/clinvar.proto +++ b/src/proto/varfish/v1/clinvar.proto @@ -48,12 +48,12 @@ message SvRecord { VariationType variation_type = 4; // The pathogenicity. Pathogenicity pathogenicity = 5; - // The variation ID. - uint32 vcv = 6; + // The RCV ID. + uint32 rcv = 6; } // ClinVar structural variant database. message SvDatabase { // The records. repeated SvRecord records = 1; -} \ No newline at end of file +} diff --git a/src/sv/query/clinvar.rs b/src/sv/query/clinvar.rs index c238da12..1adf2200 100644 --- a/src/sv/query/clinvar.rs +++ b/src/sv/query/clinvar.rs @@ -58,8 +58,8 @@ impl ClinvarSv { .collect() } - /// Returns the overlapping VCVs - pub fn overlapping_vcvs( + /// Returns the overlapping RCVs + pub fn overlapping_rcvs( &self, sv: &StructuralVariant, chrom_map: &IndexMap, @@ -86,7 +86,7 @@ impl ClinvarSv { .filter(|record| { record.pathogenicity >= min_patho.unwrap_or(Pathogenicity::Benign) as i32 }) - .map(|record| record.vcv) + .map(|record| record.rcv) .collect() } } diff --git a/src/sv/query/mod.rs b/src/sv/query/mod.rs index befb33e9..fe6fa710 100644 --- a/src/sv/query/mod.rs +++ b/src/sv/query/mod.rs @@ -124,8 +124,8 @@ struct GeneTranscriptEffects { struct ResultPayload { /// The name of the calling tool. callers: Vec, - /// The overlapping VCVs - clinvar_ovl_vcvs: Vec, + /// The overlapping RCVs + clinvar_ovl_rcvs: Vec, /// The directly overlapping genes. ovl_genes: Vec, /// Genes that are not directly overlapping but contained in overlapping @@ -327,16 +327,16 @@ fn run_query( // Get overlaps with known pathogenic SVs and ClinVar SVs result_payload.known_pathogenic = dbs.patho_dbs.overlapping_records(&schema_sv, &chrom_map); - result_payload.clinvar_ovl_vcvs = dbs + result_payload.clinvar_ovl_rcvs = dbs .clinvar_sv - .overlapping_vcvs( + .overlapping_rcvs( &schema_sv, &chrom_map, interpreter.query.clinvar_sv_min_pathogenicity, interpreter.query.clinvar_sv_min_overlap, ) .into_iter() - .map(|vcv| format!("VCV{vcv:09}")) + .map(|rcv| format!("RCV{rcv:09}")) .collect(); // Get genes in overlapping TADs diff --git a/tests/db/to-bin/varfish-db-downloader/vardbs/clinvar/clinvar-svs.jsonl b/tests/db/to-bin/varfish-db-downloader/vardbs/clinvar/clinvar-svs.jsonl new file mode 100644 index 00000000..57acaa48 --- /dev/null +++ b/tests/db/to-bin/varfish-db-downloader/vardbs/clinvar/clinvar-svs.jsonl @@ -0,0 +1,105 @@ +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000000454", "version": 5, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2009-06-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a 27-week-old male fetus with complex cortical dysplasia with other brain malformations-7 (CDCBM7; 610031), Jaglin et al. (2009) identified a heterozygous 514T-C transition in the TUBB2B gene, resulting in a ser172-to-pro (S172P) substitution. Postmortem examination showed bilateral and asymmetric frontotemporal polymicrogyria with heterotopic neuronal cells in the cerebellum and agenesis of the corpus callosum. In vitro functional expression studies showed that the S172P-mutant protein was unable to form a functional alpha/beta-tubulin heterodimer with little evidence of incorporation into well-defined microtubules."}, "citations": [{"ids": [{"source": "PubMed", "value": "19465910"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "Fallet-Bianco et al. (2014) identified a heterozygous S172P mutation in a fetus (individual 12) with microcephaly, polymicrogyria, focal neuronoglial overmigration, heterotopic neurons, complete agenesis of the corpus callosum, and mild cerebellar hypoplasia. Functional studies of the variant and studies of patient cells were not performed."}, "citations": [{"ids": [{"source": "PubMed", "value": "25059107"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000000426", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_178012.5(TUBB2B):c.514T>C (p.Ser172Pro)"}}], "canonical_spdi": "NC_000006.12:3225574:A:G", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_178012.5:c.514T>C"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_016715.1:g.7160T>C"}, {"type": "HGVS, genomic, top level", "value": "NC_000006.12:g.3225575A>G", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000006.11:g.3225809A>G", "integer_value": 37}, {"type": "HGVS, protein", "value": "Q9BVA1:p.Ser172Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_821080.1:p.Ser172Pro"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_178012.5:c.514T>C"}]}, {"type": "ProteinChange1LetterCode", "value": "S172P"}, {"type": "ProteinChange3LetterCode", "value": "SER172PRO"}], "cytogenic_locations": ["6p25.2"], "sequence_locations": [{"assembly": "GRCh38", "chr": "6", "accession": "NC_000006.12", "start": 3225575, "stop": 3225575, "display_start": 3225575, "display_stop": 3225575, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 3225575, "reference_allele_vcf": "A", "alternate_allele_vcf": "G"}, {"assembly": "GRCh37", "chr": "6", "accession": "NC_000006.11", "start": 3225809, "stop": 3225809, "display_start": 3225809, "display_stop": 3225809, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 3225809, "reference_allele_vcf": "A", "alternate_allele_vcf": "G"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "tubulin beta 2B class IIb"}}], "symbols": [{"value": {"type": "Preferred", "value": "TUBB2B"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "6", "accession": "NC_000006.12", "start": 3224277, "stop": 3227653, "display_start": 3224277, "display_stop": 3227653, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "6", "accession": "NC_000006.11", "start": 3224494, "stop": 3227967, "display_start": 3224494, "display_stop": 3227967, "strand": "-", "variant_length": 3474, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "347733"}, {"db": "OMIM", "id": "612850", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:30829"}]}], "xrefs": [{"db": "UniProtKB", "id": "Q9BVA1#VAR_063389"}, {"db": "OMIM", "id": "612850.0001", "type": "Allelic variant"}, {"db": "dbSNP", "id": "137853194", "type": "rs"}], "id": 15465}], "names": [{"value": {"type": "Preferred", "value": "NM_178012.5(TUBB2B):c.514T>C (p.Ser172Pro)"}}], "xrefs": [{"db": "ClinGen", "id": "CA250424"}], "id": 426}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Complex cortical dysplasia with other brain malformations 7"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0012399"}]}, {"value": {"type": "Alternate", "value": "Polymicrogyria, asymmetric"}, "xrefs": [{"db": "Genetic Alliance", "id": "Polymicrogyria%2C+asymmetric/9129"}]}], "symbols": [{"value": {"type": "Alternate", "value": "CDCBM7"}, "xrefs": [{"db": "OMIM", "id": "610031", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "PMGYSA"}, "xrefs": [{"db": "OMIM", "id": "610031", "type": "MIM"}]}], "attributes": [{"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "10783"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301522"}, {"source": "BookShelf", "value": "NBK1348"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "PubMed", "value": "27010057"}, {"source": "BookShelf", "value": "NBK350554"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0012399"}, {"db": "MedGen", "id": "C3552236"}, {"db": "Orphanet", "id": "300573"}, {"db": "OMIM", "id": "610031", "type": "MIM"}]}], "id": 118}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 57957}, "record_status": "current", "title": "NM_178012.5(TUBB2B):c.514T>C (p.Ser172Pro) AND Complex cortical dysplasia with other brain malformations 7", "clinvar_assertions": [{"id": 20603, "submission_id": {"local_key": "612850.0001_CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 7", "submitter": "OMIM", "title": "TUBB2B, SER172PRO _CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 7", "submitter_date": "2016-06-21"}, "clinvar_accession": {"acc": "SCV000020603", "version": 4, "type": "SCV", "date_updated": "2016-06-23", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2009-06-01"}], "external_ids": [{"db": "OMIM", "id": "612850.0001", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a 27-week-old male fetus with complex cortical dysplasia with other brain malformations-7 (CDCBM7; 610031), Jaglin et al. (2009) identified a heterozygous 514T-C transition in the TUBB2B gene, resulting in a ser172-to-pro (S172P) substitution. Postmortem examination showed bilateral and asymmetric frontotemporal polymicrogyria with heterotopic neuronal cells in the cerebellum and agenesis of the corpus callosum. In vitro functional expression studies showed that the S172P-mutant protein was unable to form a functional alpha/beta-tubulin heterodimer with little evidence of incorporation into well-defined microtubules."}, "citations": [{"ids": [{"source": "PubMed", "value": "19465910"}]}], "xrefs": [{"db": "OMIM", "id": "610031", "type": "MIM"}]}, {"attribute": {"type": "Description", "value": "Fallet-Bianco et al. (2014) identified a heterozygous S172P mutation in a fetus (individual 12) with microcephaly, polymicrogyria, focal neuronoglial overmigration, heterotopic neurons, complete agenesis of the corpus callosum, and mild cerebellar hypoplasia. Functional studies of the variant and studies of patient cells were not performed."}, "citations": [{"ids": [{"source": "PubMed", "value": "25059107"}]}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "TUBB2B, SER172PRO"}}], "attributes": [{"type": "NonHGVS", "value": "SER172PRO"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "TUBB2B"}}]}], "xrefs": [{"db": "OMIM", "id": "612850.0001", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 7"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000000455", "version": 5, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "pathogenic", "date_last_evaluated": "2021-10-02"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a 2-year-old boy with complex cortical dysplasia with other brain malformations-7 (CDCBM7; 610031) manifest as polymicrogyria, Jaglin et al. (2009) identified a heterozygous 683T-C transition in the TUBB2B gene, resulting in a leu228-to-pro (L228P) substitution. The patient had microcephaly, severe neuromotor impairment, no visual contact, and infantile seizures. Brain imaging showed polymicrogyria predominantly in the frontal and temporal lobes, including the hippocampus. Other abnormal features included a dysmorphic caudate and striatum, cerebellar vermian dysplasia with hypoplasia, agenesis of the corpus callosum, and mild hypoplasia of the brainstem. In vitro functional expression studies showed that the L228P-mutant protein had impaired ability to form a functional alpha/beta-tubulin heterodimer. However, the mutant protein appeared to be incorporated into microtubules."}, "citations": [{"ids": [{"source": "PubMed", "value": "19465910"}], "type": "general"}]}]}, {"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "number_tested": 1}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}]}], "measures": {"type": "Variant", "acc": "VCV000000427", "version": 2, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_178012.5(TUBB2B):c.683T>C (p.Leu228Pro)"}}], "canonical_spdi": "NC_000006.12:3225405:A:G", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_178012.5:c.683T>C"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_016715.1:g.7329T>C"}, {"type": "HGVS, genomic, top level", "value": "NC_000006.12:g.3225406A>G", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000006.11:g.3225640A>G", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_178012.4:c.683T>C"}, {"type": "HGVS, protein", "value": "Q9BVA1:p.Leu228Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_821080.1:p.Leu228Pro"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_178012.5:c.683T>C"}]}, {"type": "ProteinChange1LetterCode", "value": "L228P"}, {"type": "ProteinChange3LetterCode", "value": "LEU228PRO"}], "cytogenic_locations": ["6p25.2"], "sequence_locations": [{"assembly": "GRCh38", "chr": "6", "accession": "NC_000006.12", "start": 3225406, "stop": 3225406, "display_start": 3225406, "display_stop": 3225406, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 3225406, "reference_allele_vcf": "A", "alternate_allele_vcf": "G"}, {"assembly": "GRCh37", "chr": "6", "accession": "NC_000006.11", "start": 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"previous"}], "xrefs": [{"db": "Gene", "id": "347733"}, {"db": "OMIM", "id": "612850", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:30829"}]}], "xrefs": [{"db": "UniProtKB", "id": "Q9BVA1#VAR_063392"}, {"db": "OMIM", "id": "612850.0002", "type": "Allelic variant"}, {"db": "dbSNP", "id": "137853195", "type": "rs"}], "id": 15466}], "names": [{"value": {"type": "Preferred", "value": "NM_178012.5(TUBB2B):c.683T>C (p.Leu228Pro)"}}], "xrefs": [{"db": "ClinGen", "id": "CA250425"}], "id": 427}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Complex cortical dysplasia with other brain malformations 7"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0012399"}]}, {"value": {"type": "Alternate", "value": "Polymicrogyria, asymmetric"}, "xrefs": [{"db": "Genetic Alliance", "id": "Polymicrogyria%2C+asymmetric/9129"}]}], "symbols": [{"value": {"type": "Alternate", "value": "CDCBM7"}, "xrefs": [{"db": "OMIM", "id": "610031", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "PMGYSA"}, "xrefs": [{"db": "OMIM", "id": "610031", "type": "MIM"}]}], "attributes": [{"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "10783"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301522"}, {"source": "BookShelf", "value": "NBK1348"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "PubMed", "value": "27010057"}, {"source": "BookShelf", "value": "NBK350554"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0012399"}, {"db": "MedGen", "id": "C3552236"}, {"db": "Orphanet", "id": "300573"}, {"db": "OMIM", "id": "610031", "type": "MIM"}]}], "id": 118}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 57958}, "record_status": "current", "title": "NM_178012.5(TUBB2B):c.683T>C (p.Leu228Pro) AND Complex cortical dysplasia with other brain malformations 7", "clinvar_assertions": [{"id": 20604, "submission_id": {"local_key": "612850.0002_CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 7", "submitter": "OMIM", "title": "TUBB2B, LEU228PRO _CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 7", "submitter_date": "2016-06-21"}, "clinvar_accession": {"acc": "SCV000020604", "version": 3, "type": "SCV", "date_updated": "2016-06-23", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2009-06-01"}], "external_ids": [{"db": "OMIM", "id": "612850.0002", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a 2-year-old boy with complex cortical dysplasia with other brain malformations-7 (CDCBM7; 610031) manifest as polymicrogyria, Jaglin et al. (2009) identified a heterozygous 683T-C transition in the TUBB2B gene, resulting in a leu228-to-pro (L228P) substitution. The patient had microcephaly, severe neuromotor impairment, no visual contact, and infantile seizures. Brain imaging showed polymicrogyria predominantly in the frontal and temporal lobes, including the hippocampus. Other abnormal features included a dysmorphic caudate and striatum, cerebellar vermian dysplasia with hypoplasia, agenesis of the corpus callosum, and mild hypoplasia of the brainstem. In vitro functional expression studies showed that the L228P-mutant protein had impaired ability to form a functional alpha/beta-tubulin heterodimer. However, the mutant protein appeared to be incorporated into microtubules."}, "citations": [{"ids": [{"source": "PubMed", "value": "19465910"}]}], "xrefs": [{"db": "OMIM", "id": "610031", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "TUBB2B, LEU228PRO"}}], "attributes": [{"type": "NonHGVS", "value": "LEU228PRO"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "TUBB2B"}}]}], "xrefs": [{"db": "OMIM", "id": "612850.0002", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 7"}}]}]}}, {"id": 3950553, "submission_id": {"local_key": "6-3225640-A-G", "submitter": "3billion", "submitted_assembly": "GRCh37", "submitter_date": "2021-11-05"}, "clinvar_accession": {"acc": "SCV002012213", "version": 1, "type": "SCV", "date_updated": "2021-11-11", "date_created": "2021-11-11", "org_id": "507830", "org_type": "primary", "org_category": "other"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["pathogenic"], "citations": [{"ids": [{"source": "PubMed", "value": "19465910"}]}], "comments": [{"text": "Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in a similarly affected individual (ClinVar ID: VCV000000427.1, PMID: 19465910, PS1, PS2). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.919, 3Cnet: 0.997, PP3). Patient's phenotype is considered compatible with Cortical Dysplasia, Complex, with Other Brain Malformations 7 (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline."}], "date_last_evaluated": "2021-10-02"}], "external_ids": [{"db": "3billion", "id": "NIPA038"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "ACMG Guidelines, 2015"}, "citations": [{"ids": [{"source": "PubMed", "value": "25741868"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "number_tested": 1, "proband": "yes"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "SingleHeterozygote", "integer_value": 1}}], "traits": {"type": "Finding", "traits": [{"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0002194"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0000609"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0007206"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0100842"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0001290"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0000750"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0001328"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0011231"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0001360"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0000574"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0001250"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0001249"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0001274"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0002539"}]}]}}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_178012.4:c.683T>C"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "TUBB2B"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "OMIM", "id": "610031", "type": "MIM"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000000456", "version": 4, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2009-06-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a 37-year-old man with complex cortical dysplasia with other brain malformations-7 (CDCBM7; 610031) manifest as polymicrogyria, Jaglin et al. (2009) identified a heterozygous 793T-C transition in the TUBB2B gene, resulting in a phe265-to-leu (F265L) substitution. He had microcephaly, severe mental retardation, and seizures, but no neuromotor impairment. Brain imaging showed asymmetric polymicrogyria predominantly in the left frontal, parietal, and temporal lobes, including the hippocampus. Other abnormal features were a dysmorphic caudate and striatum, severe cerebellar atrophy, partial posterior agenesis of the corpus callosum, and hypoplasia of the pons. In vitro functional expression assays showed that the F265L-mutant protein had markedly impaired ability to form alpha/beta-tubulin heterodimers with little evidence of incorporation into well-defined microtubules. Jaglin et al. (2009) noted that severe defect observed in vitro and the relatively mild phenotype of this patient, suggested that there is no simple correlation between in vitro and clinical phenotype."}, "citations": [{"ids": [{"source": "PubMed", "value": "19465910"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000000428", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_178012.5(TUBB2B):c.793T>C (p.Phe265Leu)"}}], "canonical_spdi": "NC_000006.12:3225295:A:G", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_178012.5:c.793T>C"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_016715.1:g.7439T>C"}, {"type": "HGVS, genomic, top level", "value": "NC_000006.12:g.3225296A>G", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000006.11:g.3225530A>G", "integer_value": 37}, {"type": "HGVS, protein", "value": "Q9BVA1:p.Phe265Leu"}, {"type": "HGVS, protein, RefSeq", 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"version": 3, "type": "SCV", "date_updated": "2018-12-16", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2012-04-01"}], "external_ids": [{"db": "OMIM", "id": "603846.0002", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "For discussion of the arg199-to-trp (R199W) mutation in the NDUFS3 gene that was found in compound heterozygous state in a patient with complex I deficiency (MC1DN8; 618230) manifesting as Leigh syndrome (see 256000) by Benit et al. (2004), see 603846.0001."}, "citations": [{"ids": [{"source": "PubMed", "value": "14729820"}]}], "xrefs": [{"db": "OMIM", "id": "618230", "type": "MIM"}, {"db": "OMIM", "id": "256000", "type": "MIM"}]}, {"attribute": {"type": "Description", "value": "Haack et al. (2012) identified a homozygous 532C-T transition in the NDUFS3 gene, resulting in an R199W substitution, in a patient with MC1DN8. The mutation (rs104894270) was identified by exome sequencing. The patient had encephalopathy, myopathy, developmental delay, and lactic acidosis; Leigh syndrome was not noted. Complex I activity was 28% in muscle and 36% in fibroblasts, and there was a decrease in fully assembled complex I."}, "citations": [{"ids": [{"source": "PubMed", "value": "22499348"}]}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "NDUFS3, ARG199TRP (rs104894270)"}}], "attributes": [{"type": "NonHGVS", "value": "ARG199TRP (rs104894270)"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "NDUFS3"}}]}], "xrefs": [{"db": "OMIM", "id": "603846.0002", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 8"}}]}]}}, {"id": 1823216, "submission_id": {"local_key": "NM_004551.2:c.595C>T|OMIM:618230", "submitter": "SIB Swiss Institute of Bioinformatics", "submitted_assembly": "not applicable", "submitter_date": "2019-03-27"}, "clinvar_accession": {"acc": "SCV000930056", "version": 1, "type": "SCV", "date_updated": "2019-08-04", "date_created": "2019-08-04", "org_id": "506146", "org_type": "primary", "org_category": "other"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["likely pathogenic"], "citations": [{"ids": [{"source": "PubMed", "value": "14729820"}]}, {"ids": [{"source": "PubMed", "value": "22499348"}]}, {"ids": [{"source": "PubMed", "value": "30140060"}]}], "comments": [{"text": "This variant is interpreted as a Likely pathogenic for Mitochondrial complex I deficiency, nuclear type 8, autosomal recessive. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 : Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:14729820). PS3 : Well-established functional studies show a deleterious effect (PMID:22499348)."}], "date_last_evaluated": "2019-01-23"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "ACMG Guidelines, 2015"}, "citations": [{"ids": [{"source": "PubMed", "value": "25741868"}]}]}], "observed_in": [{"sample": {"origin": "unknown", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["curation"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_004551.2:c.595C>T"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "NDUFS3"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "OMIM", "id": "618230", "type": "MIM"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000006538", "version": 3, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2001-09-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In 2 affected sibs and 1 fetus in a consanguineous family with mitochondrial complex III deficiency nuclear type 1 (MC3DN1; 124000) characterized by neonatal tubulopathy, encephalopathy, and liver failure, de Lonlay et al. (2001) identified a homozygous 830G-A transition in the BCS1L gene, resulting in a ser277-to-asp (S277N) substitution."}, "citations": [{"ids": [{"source": "PubMed", "value": "11528392"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000006163", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_001079866.2(BCS1L):c.830G>A (p.Ser277Asn)"}}], "canonical_spdi": "NC_000002.12:218662619:G:A", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001371452.1:c.329G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371453.1:c.329G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371454.1:c.329G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371455.1:c.329G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371456.1:c.329G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001374086.1:c.329G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001318836.2:c.470G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371451.1:c.470G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001079866.2:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001257342.2:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001257343.2:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001257344.2:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001320717.2:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371443.1:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371444.1:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371446.1:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371447.1:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371448.1:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371449.1:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371450.1:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001374085.1:c.830G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_004328.5:c.830G>A"}, {"type": "HGVS, genomic, LRG", "value": "LRG_539:g.7965G>A"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_033099.1:g.1921C>T"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_008018.1:g.7965G>A"}, {"type": "HGVS, genomic, top level", "value": "NC_000002.12:g.218662620G>A", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000002.11:g.219527343G>A", "integer_value": 37}, {"type": "HGVS, non-coding", "value": "NR_163955.1:n.1837G>A"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein", "value": "Q9Y276:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358381.1:p.Ser110Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358382.1:p.Ser110Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358383.1:p.Ser110Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358384.1:p.Ser110Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358385.1:p.Ser110Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001361015.1:p.Ser110Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001305765.1:p.Ser157Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358380.1:p.Ser157Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001073335.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001244271.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001244272.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001244273.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001307646.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358372.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358373.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358375.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358376.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358377.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358378.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358379.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001361014.1:p.Ser277Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_004319.1:p.Ser277Asn"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001079866.2:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001257342.2:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001257343.2:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001257344.2:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001318836.2:c.470G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001320717.2:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371443.1:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371444.1:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371446.1:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371447.1:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371448.1:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371449.1:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371450.1:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371451.1:c.470G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371452.1:c.329G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371453.1:c.329G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371454.1:c.329G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371455.1:c.329G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371456.1:c.329G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001374085.1:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001374086.1:c.329G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_004328.5:c.830G>A"}]}, {"type": "MolecularConsequence", "value": "non-coding transcript variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001619"}, {"db": "RefSeq", "id": "NR_163955.1:n.1837G>A"}]}, {"type": "ProteinChange1LetterCode", "value": "S110N"}, {"type": "ProteinChange1LetterCode", "value": "S157N"}, {"type": "ProteinChange1LetterCode", "value": "S277N"}, {"type": "ProteinChange3LetterCode", "value": "SER277ASN"}], "cytogenic_locations": ["2q35"], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 218662620, "stop": 218662620, "display_start": 218662620, "display_stop": 218662620, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 218662620, "reference_allele_vcf": "G", "alternate_allele_vcf": "A"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 219527343, "stop": 219527343, "display_start": 219527343, "display_stop": 219527343, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 219527343, "reference_allele_vcf": "G", "alternate_allele_vcf": "A"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone"}}], "symbols": [{"value": {"type": "Preferred", "value": "BCS1L"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 218658743, "stop": 218663443, "display_start": 218658743, "display_stop": 218663443, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 219524378, "stop": 219528165, "display_start": 219524378, "display_stop": 219528165, "strand": "+", "variant_length": 3788, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "617"}, {"db": "OMIM", "id": "603647", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:1020"}]}], "xrefs": [{"db": "UniProtKB", "id": "Q9Y276#VAR_018162"}, {"db": "OMIM", "id": "603647.0001", "type": "Allelic variant"}, {"db": "dbSNP", "id": "121908571", "type": "rs"}], "id": 21202}], "names": [{"value": {"type": "Preferred", "value": "NM_001079866.2(BCS1L):c.830G>A (p.Ser277Asn)"}}], "xrefs": [{"db": "ClinGen", "id": "CA117984"}], "id": 6163}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Mitochondrial complex III deficiency nuclear type 1"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0007415"}]}, {"value": {"type": "Alternate", "value": "Complex 3 mitochondrial respiratory chain deficiency"}}], "symbols": [{"value": {"type": "Alternate", "value": "MC3DN1"}, "xrefs": [{"db": "OMIM", "id": "124000", "type": "MIM"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0007415"}, {"db": "MedGen", "id": "C3541471"}, {"db": "Orphanet", "id": "254902"}, {"db": "OMIM", "id": "124000", "type": "MIM"}]}], "id": 180}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 64041}, "record_status": "current", "title": "NM_001079866.2(BCS1L):c.830G>A (p.Ser277Asn) AND Mitochondrial complex III deficiency nuclear type 1", "clinvar_assertions": [{"id": 26721, "submission_id": {"local_key": "603647.0001_MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1", "submitter": "OMIM", "title": "BCS1L, SER277ASN_MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1", "submitter_date": "2013-04-08"}, "clinvar_accession": {"acc": "SCV000026721", "version": 2, "type": "SCV", "date_updated": "2013-04-10", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2001-09-01"}], "external_ids": [{"db": "OMIM", "id": "603647.0001", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In 2 affected sibs and 1 fetus in a consanguineous family with mitochondrial complex III deficiency nuclear type 1 (MC3DN1; 124000) characterized by neonatal tubulopathy, encephalopathy, and liver failure, de Lonlay et al. (2001) identified a homozygous 830G-A transition in the BCS1L gene, resulting in a ser277-to-asp (S277N) substitution."}, "citations": [{"ids": [{"source": "PubMed", "value": "11528392"}]}], "xrefs": [{"db": "OMIM", "id": "124000", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "BCS1L, SER277ASN"}}], "attributes": [{"type": "NonHGVS", "value": "SER277ASN"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "BCS1L"}}]}], "xrefs": [{"db": "OMIM", "id": "603647.0001", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000006540", "version": 5, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2001-09-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a boy of Turkish origin with complex III deficiency (MC3DN1; 124000) born to nonconsanguineous parents, de Lonlay et al. (2001) identified compound heterozygosity for 2 mutations in the BCS1L gene: a 464C-G transversion in exon 3 of the BCS1L gene, resulting in an arg155-to-pro (R155P) substitution, and a 1057G-A transition in exon 7, resulting in a val353-to-met (V353M; 603647.0004) substitution."}, "citations": [{"ids": [{"source": "PubMed", "value": "11528392"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000006165", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_001079866.2(BCS1L):c.464G>C (p.Arg155Pro)"}}], "canonical_spdi": "NC_000002.12:218661761:G:C", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001371452.1:c.-38G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371453.1:c.-38G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371454.1:c.-38G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371455.1:c.-38G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371456.1:c.-38G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001374086.1:c.-38G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001318836.2:c.104G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371451.1:c.104G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001079866.2:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001257342.2:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001257343.2:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001257344.2:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001320717.2:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371443.1:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371444.1:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371446.1:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371447.1:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371448.1:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371449.1:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371450.1:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001374085.1:c.464G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_004328.5:c.464G>C"}, {"type": "HGVS, genomic, LRG", "value": "LRG_539:g.7107G>C"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_033099.1:g.2779C>G"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_008018.1:g.7107G>C"}, {"type": "HGVS, genomic, top level", "value": "NC_000002.12:g.218661762G>C", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000002.11:g.219526485G>C", "integer_value": 37}, {"type": "HGVS, non-coding", "value": "NR_163955.1:n.1476G>C"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein", "value": "Q9Y276:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001073335.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001244271.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001244272.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001244273.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001307646.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358372.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358373.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358375.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358376.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358377.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358378.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358379.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001361014.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_004319.1:p.Arg155Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001305765.1:p.Arg35Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358380.1:p.Arg35Pro"}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001371452.1:c.-38G>C"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001371453.1:c.-38G>C"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001371454.1:c.-38G>C"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001371455.1:c.-38G>C"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001371456.1:c.-38G>C"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001374086.1:c.-38G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001079866.2:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001257342.2:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001257343.2:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001257344.2:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001318836.2:c.104G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001320717.2:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371443.1:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371444.1:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371446.1:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371447.1:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371448.1:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371449.1:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371450.1:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371451.1:c.104G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001374085.1:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_004328.5:c.464G>C"}]}, {"type": "MolecularConsequence", "value": "non-coding transcript variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001619"}, {"db": "RefSeq", "id": "NR_163955.1:n.1476G>C"}]}, {"type": "ProteinChange1LetterCode", "value": "R155P"}, {"type": "ProteinChange1LetterCode", "value": "R35P"}, {"type": "ProteinChange3LetterCode", "value": "ARG155PRO"}], "cytogenic_locations": ["2q35"], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 218661762, "stop": 218661762, "display_start": 218661762, "display_stop": 218661762, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 218661762, "reference_allele_vcf": "G", "alternate_allele_vcf": "C"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 219526485, "stop": 219526485, "display_start": 219526485, "display_stop": 219526485, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 219526485, "reference_allele_vcf": "G", "alternate_allele_vcf": "C"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone"}}], "symbols": [{"value": {"type": "Preferred", "value": "BCS1L"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 218658743, "stop": 218663443, "display_start": 218658743, "display_stop": 218663443, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 219524378, "stop": 219528165, "display_start": 219524378, "display_stop": 219528165, "strand": "+", "variant_length": 3788, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "617"}, {"db": "OMIM", "id": "603647", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:1020"}]}], "xrefs": [{"db": "UniProtKB", "id": "Q9Y276#VAR_018161"}, {"db": "OMIM", "id": "603647.0003", "type": "Allelic variant"}, {"db": "dbSNP", "id": "121908573", "type": "rs"}], "id": 21204}], "names": [{"value": {"type": "Preferred", "value": "NM_001079866.2(BCS1L):c.464G>C (p.Arg155Pro)"}}], "xrefs": [{"db": "ClinGen", "id": "CA117994"}], "id": 6165}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Mitochondrial complex III deficiency nuclear type 1"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0007415"}]}, {"value": {"type": "Alternate", "value": "Complex 3 mitochondrial respiratory chain deficiency"}}], "symbols": [{"value": {"type": "Alternate", "value": "MC3DN1"}, "xrefs": [{"db": "OMIM", "id": "124000", "type": "MIM"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0007415"}, {"db": "MedGen", "id": "C3541471"}, {"db": "Orphanet", "id": "254902"}, {"db": "OMIM", "id": "124000", "type": "MIM"}]}], "id": 180}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 64043}, "record_status": "current", "title": "NM_001079866.2(BCS1L):c.464G>C (p.Arg155Pro) AND Mitochondrial complex III deficiency nuclear type 1", "clinvar_assertions": [{"id": 26723, "submission_id": {"local_key": "603647.0003_MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1", "submitter": "OMIM", "title": "BCS1L, ARG155PRO_MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1", "submitter_date": "2017-01-17"}, "clinvar_accession": {"acc": "SCV000026723", "version": 4, "type": "SCV", "date_updated": "2017-01-20", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2001-09-01"}], "external_ids": [{"db": "OMIM", "id": "603647.0003", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a boy of Turkish origin with complex III deficiency (MC3DN1; 124000) born to nonconsanguineous parents, de Lonlay et al. (2001) identified compound heterozygosity for 2 mutations in the BCS1L gene: a 464C-G transversion in exon 3 of the BCS1L gene, resulting in an arg155-to-pro (R155P) substitution, and a 1057G-A transition in exon 7, resulting in a val353-to-met (V353M; 603647.0004) substitution."}, "citations": [{"ids": [{"source": "PubMed", "value": "11528392"}]}], "xrefs": [{"db": "OMIM", "id": "124000", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "BCS1L, ARG155PRO"}}], "attributes": [{"type": "NonHGVS", "value": "ARG155PRO"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "BCS1L"}}]}], "xrefs": [{"db": "OMIM", "id": "603647.0003", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000006549", "version": 5, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2009-02-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a 4-year-old Spanish boy with isolated mitochondrial complex III deficiency (MC3DN1; 124000), Blazquez et al. (2009) identified a homozygous 148A-G transition in exon 1 of the BCS1L gene, resulting in a thr50-to-ala (T50A) substitution in the mitochondrial sorting sequence. He presented at 6 months of age with psychomotor retardation, failure to thrive, hypotonia, lactic acidosis, and hepatic dysfunction. Physical examination showed unstable head support, poor eye fixation, coarse facies, and epicanthus. There was hypertrichosis of the frontal head zone and limbs, and excessive fat distribution in the upper back, neck, hands and feet, with almost no fat on the limbs. Respiratory chain activity in muscle and fibroblasts showed an isolated complex III defect (58% of normal in muscle, 93% in fibroblasts). At age 4 years, he still showed psychomotor retardation, had developed mild sensorineural hearing loss, and persistent lactic acidemia, but renal function, hair, and iron metabolism were normal. Brain MRI was normal. The mutation was not found in 400 control alleles, and each unaffected parent was heterozygous for the mutation."}, "citations": [{"ids": [{"source": "PubMed", "value": "19162478"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000006173", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_001079866.2(BCS1L):c.148A>G (p.Thr50Ala)"}}], "canonical_spdi": "NC_000002.12:218661134:A:G", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001371453.1:c.-329A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371454.1:c.-329A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371455.1:c.-329A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371456.1:c.-329A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001374086.1:c.-329A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001318836.2:c.-40-271A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371451.1:c.-40-271A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371452.1:c.-41-624A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001079866.2:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001257342.2:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001257343.2:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001257344.2:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001320717.2:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371443.1:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371444.1:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371446.1:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371447.1:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371448.1:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371449.1:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001371450.1:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001374085.1:c.148A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_004328.5:c.148A>G"}, {"type": "HGVS, genomic, LRG", "value": "LRG_539:g.6480A>G"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_033099.1:g.3406T>C"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_008018.1:g.6480A>G"}, {"type": "HGVS, genomic, top level", "value": "NC_000002.12:g.218661135A>G", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000002.11:g.219525858A>G", "integer_value": 37}, {"type": "HGVS, non-coding", "value": "NR_163955.1:n.1160A>G"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein", "value": "Q9Y276:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001073335.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001244271.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001244272.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001244273.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001307646.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358372.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358373.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358375.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358376.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358377.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358378.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001358379.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001361014.1:p.Thr50Ala"}, {"type": "HGVS, protein, RefSeq", "value": "NP_004319.1:p.Thr50Ala"}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001371453.1:c.-329A>G"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001371454.1:c.-329A>G"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001371455.1:c.-329A>G"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001371456.1:c.-329A>G"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001374086.1:c.-329A>G"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001318836.2:c.-40-271A>G"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001371451.1:c.-40-271A>G"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001371452.1:c.-41-624A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001079866.2:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001257342.2:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001257343.2:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001257344.2:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001320717.2:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371443.1:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371444.1:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371446.1:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371447.1:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371448.1:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371449.1:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001371450.1:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001374085.1:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_004328.5:c.148A>G"}]}, {"type": "MolecularConsequence", "value": "non-coding transcript variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001619"}, {"db": "RefSeq", "id": "NR_163955.1:n.1160A>G"}]}, {"type": "ProteinChange1LetterCode", "value": "T50A"}, {"type": "ProteinChange3LetterCode", "value": "THR50ALA"}], "cytogenic_locations": ["2q35"], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 218661135, "stop": 218661135, "display_start": 218661135, "display_stop": 218661135, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 218661135, "reference_allele_vcf": "A", "alternate_allele_vcf": "G"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 219525858, "stop": 219525858, "display_start": 219525858, "display_stop": 219525858, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 219525858, "reference_allele_vcf": "A", "alternate_allele_vcf": "G"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone"}}], "symbols": [{"value": {"type": "Preferred", "value": "BCS1L"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 218658743, "stop": 218663443, "display_start": 218658743, "display_stop": 218663443, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 219524378, "stop": 219528165, "display_start": 219524378, "display_stop": 219528165, "strand": "+", "variant_length": 3788, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "617"}, {"db": "OMIM", "id": "603647", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:1020"}]}], "xrefs": [{"db": "UniProtKB", "id": "Q9Y276#VAR_064615"}, {"db": "OMIM", "id": "603647.0011", "type": "Allelic variant"}, {"db": "dbSNP", "id": "121908580", "type": "rs"}], "id": 21212}], "names": [{"value": {"type": "Preferred", "value": "NM_001079866.2(BCS1L):c.148A>G (p.Thr50Ala)"}}], "xrefs": [{"db": "ClinGen", "id": "CA118036"}], "id": 6173}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Mitochondrial complex III deficiency nuclear type 1"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0007415"}]}, {"value": {"type": "Alternate", "value": "Complex 3 mitochondrial respiratory chain deficiency"}}], "symbols": [{"value": {"type": "Alternate", "value": "MC3DN1"}, "xrefs": [{"db": "OMIM", "id": "124000", "type": "MIM"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0007415"}, {"db": "MedGen", "id": "C3541471"}, {"db": "Orphanet", "id": "254902"}, {"db": "OMIM", "id": "124000", "type": "MIM"}]}], "id": 180}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 64052}, "record_status": "current", "title": "NM_001079866.2(BCS1L):c.148A>G (p.Thr50Ala) AND Mitochondrial complex III deficiency nuclear type 1", "clinvar_assertions": [{"id": 26732, "submission_id": {"local_key": "603647.0011_MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1", "submitter": "OMIM", "title": "BCS1L, THR50ALA_MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1", "submitter_date": "2017-01-17"}, "clinvar_accession": {"acc": "SCV000026732", "version": 4, "type": "SCV", "date_updated": "2017-01-20", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2009-02-01"}], "external_ids": [{"db": "OMIM", "id": "603647.0011", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a 4-year-old Spanish boy with isolated mitochondrial complex III deficiency (MC3DN1; 124000), Blazquez et al. (2009) identified a homozygous 148A-G transition in exon 1 of the BCS1L gene, resulting in a thr50-to-ala (T50A) substitution in the mitochondrial sorting sequence. He presented at 6 months of age with psychomotor retardation, failure to thrive, hypotonia, lactic acidosis, and hepatic dysfunction. Physical examination showed unstable head support, poor eye fixation, coarse facies, and epicanthus. There was hypertrichosis of the frontal head zone and limbs, and excessive fat distribution in the upper back, neck, hands and feet, with almost no fat on the limbs. Respiratory chain activity in muscle and fibroblasts showed an isolated complex III defect (58% of normal in muscle, 93% in fibroblasts). At age 4 years, he still showed psychomotor retardation, had developed mild sensorineural hearing loss, and persistent lactic acidemia, but renal function, hair, and iron metabolism were normal. Brain MRI was normal. The mutation was not found in 400 control alleles, and each unaffected parent was heterozygous for the mutation."}, "citations": [{"ids": [{"source": "PubMed", "value": "19162478"}]}], "xrefs": [{"db": "OMIM", "id": "124000", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "BCS1L, THR50ALA"}}], "attributes": [{"type": "NonHGVS", "value": "THR50ALA"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "BCS1L"}}]}], "xrefs": [{"db": "OMIM", "id": "603647.0011", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000007943", "version": 4, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2004-05-25"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a patient with late onset of mitochondrial complex I deficiency nuclear type 2 (MC1DN2; 618222) manifesting as Leigh syndrome (see 256000), Procaccio and Wallace (2004) identified compound heterozygosity for 2 mutations in the NDUFS8 gene: a 254C-T transition, resulting in a pro85-to-leu (P85L) substitution, and a 413G-A transition, resulting in an arg138-to-his (R138H; 602141.0004) substitution. The patient first developed walking difficulties at age 7 years, which progressed to balance impairment, dysarthria, mild dystonic posture, and nystagmus. Brain imaging showed bilateral symmetric lesions in the putamen. Complex I activity in the patient's skeletal muscle and lymphoblasts was reduced to 31% and 43% of controls, respectively. Western blot analysis showed decreased amounts of the NDUFS8 protein and other nuclear complex I subunits, suggesting that NDUFS8 may play a role in complex I assembly. Procaccio and Wallace (2004) suggested that the mild phenotype in this patient may have resulted from partial preservation of electron transport, as neither mutation disrupted the cysteine motifs thought to be associated with 4Fe-4S clusters."}, "citations": [{"ids": [{"source": "PubMed", "value": "15159508"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000007513", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_002496.4(NDUFS8):c.254C>T (p.Pro85Leu)"}}], "canonical_spdi": "NC_000011.10:68033164:C:T", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_002496.4:c.254C>T"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_017040.1:g.7549C>T"}, {"type": "HGVS, genomic, top level", "value": "NC_000011.10:g.68033165C>T", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000011.9:g.67800632C>T", "integer_value": 37}, {"type": "HGVS, protein, RefSeq", "value": "NP_002487.1:p.Pro85Leu"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_002496.4:c.254C>T"}]}, {"type": "ProteinChange1LetterCode", "value": "P85L"}, {"type": "ProteinChange3LetterCode", "value": "PRO85LEU"}], "cytogenic_locations": ["11q13.2"], "sequence_locations": [{"assembly": "GRCh38", "chr": "11", "accession": "NC_000011.10", "start": 68033165, "stop": 68033165, "display_start": 68033165, "display_stop": 68033165, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 68033165, "reference_allele_vcf": "C", "alternate_allele_vcf": "T"}, {"assembly": "GRCh37", "chr": "11", "accession": "NC_000011.9", "start": 67800632, "stop": 67800632, "display_start": 67800632, "display_stop": 67800632, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 67800632, "reference_allele_vcf": "C", "alternate_allele_vcf": "T"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "NADH:ubiquinone oxidoreductase core subunit S8"}}], "symbols": [{"value": {"type": "Preferred", "value": "NDUFS8"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "11", "accession": "NC_000011.10", "start": 68030681, "stop": 68036644, "display_start": 68030681, "display_stop": 68036644, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "11", "accession": "NC_000011.9", "start": 67798083, "stop": 67804113, "display_start": 67798083, "display_stop": 67804113, "strand": "+", "variant_length": 6031, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "4728"}, {"db": "OMIM", "id": "602141", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:7715"}]}], "xrefs": [{"db": "OMIM", "id": "602141.0003", "type": "Allelic variant"}, {"db": "dbSNP", "id": "121912639", "type": "rs"}], "id": 22552}], "names": [{"value": {"type": "Preferred", "value": "NM_002496.4(NDUFS8):c.254C>T (p.Pro85Leu)"}}], "xrefs": [{"db": "ClinGen", "id": "CA118855"}], "id": 7513}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Mitochondrial complex 1 deficiency, nuclear type 2"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0032606"}]}, {"value": {"type": "Alternate", "value": "MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 2"}, "xrefs": [{"db": "OMIM", "id": "618222", "type": "MIM"}, {"db": "OMIM", "id": "602141.0001", "type": "Allelic variant"}, {"db": "OMIM", "id": "602141.0002", "type": "Allelic variant"}, {"db": "OMIM", "id": "602141.0003", "type": "Allelic variant"}, {"db": "OMIM", "id": "602141.0004", "type": "Allelic variant"}, {"db": "OMIM", "id": "602141.0005", "type": "Allelic variant"}, {"db": "OMIM", "id": "602141.0006", "type": "Allelic variant"}, {"db": "OMIM", "id": "602141.0007", "type": "Allelic variant"}]}], "symbols": [{"value": {"type": "Alternate", "value": "MC1DN2"}, "xrefs": [{"db": "OMIM", "id": "618222", "type": "MIM"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0032606"}, {"db": "MedGen", "id": "C4748737"}, {"db": "OMIM", "id": "618222", "type": "MIM"}]}], "id": 45314}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 65446}, "record_status": "current", "title": "NM_002496.4(NDUFS8):c.254C>T (p.Pro85Leu) AND Mitochondrial complex 1 deficiency, nuclear type 2", "clinvar_assertions": [{"id": 28148, "submission_id": {"local_key": "602141.0003_MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 2", "submitter": "OMIM", "title": "NDUFS8, PRO85LEU_MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 2", "submitter_date": "2018-12-13"}, "clinvar_accession": {"acc": "SCV000028148", "version": 3, "type": "SCV", "date_updated": "2018-12-16", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2004-05-25"}], "external_ids": [{"db": "OMIM", "id": "602141.0003", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a patient with late onset of mitochondrial complex I deficiency nuclear type 2 (MC1DN2; 618222) manifesting as Leigh syndrome (see 256000), Procaccio and Wallace (2004) identified compound heterozygosity for 2 mutations in the NDUFS8 gene: a 254C-T transition, resulting in a pro85-to-leu (P85L) substitution, and a 413G-A transition, resulting in an arg138-to-his (R138H; 602141.0004) substitution. The patient first developed walking difficulties at age 7 years, which progressed to balance impairment, dysarthria, mild dystonic posture, and nystagmus. Brain imaging showed bilateral symmetric lesions in the putamen. Complex I activity in the patient's skeletal muscle and lymphoblasts was reduced to 31% and 43% of controls, respectively. Western blot analysis showed decreased amounts of the NDUFS8 protein and other nuclear complex I subunits, suggesting that NDUFS8 may play a role in complex I assembly. Procaccio and Wallace (2004) suggested that the mild phenotype in this patient may have resulted from partial preservation of electron transport, as neither mutation disrupted the cysteine motifs thought to be associated with 4Fe-4S clusters."}, "citations": [{"ids": [{"source": "PubMed", "value": "15159508"}]}], "xrefs": [{"db": "OMIM", "id": "618222", "type": "MIM"}, {"db": "OMIM", "id": "256000", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "NDUFS8, PRO85LEU"}}], "attributes": [{"type": "NonHGVS", "value": "PRO85LEU"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "NDUFS8"}}]}], "xrefs": [{"db": "OMIM", "id": "602141.0003", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 2"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000008458", "version": 3, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "1999-03-16"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a family with Holt-Oram syndrome (HOS; 142900), Basson et al. (1999) identified a gly80-to-arg substitution in the TBX5 gene. They found that this mutation caused significant cardiac malformations but only minor skeletal abnormalities."}, "citations": [{"ids": [{"source": "PubMed", "value": "10077612"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000007994", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_181486.4(TBX5):c.238G>A (p.Gly80Arg)"}}], "canonical_spdi": "NC_000012.12:114401829:C:T", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_670t1:c.238G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000192.3:c.238G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_181486.4:c.238G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_080717.4:c.88G>A"}, {"type": "HGVS, genomic, LRG", "value": "LRG_670:g.11613G>A"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_007373.1:g.11613G>A"}, {"type": "HGVS, genomic, top level", "value": "NC_000012.12:g.114401830C>T", "integer_value": 38}, {"type": "HGVS, 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Only the older 2 patients had retinitis pigmentosa."}, "citations": [{"ids": [{"source": "PubMed", "value": "20797687"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000000025", "version": 1, "measures": [{"type": "indel", "names": [{"value": {"type": "Preferred", "value": "NM_015600.4(ABHD12):c.-6898_191+7002delinsCC"}}], "attributes": [{"type": "HGVS, genomic, top level", "value": "NC_000020.11:g.25383511_25397600delinsG", "integer_value": 38}, {"type": "HGVS, genomic, top level", "value": "NC_000020.11:g.25383511_25397601delinsGG", "integer_value": 38}, {"type": "HGVS, genomic, top level, other", "value": "NC_000020.10:g.25364147_25378237del14091insGG", "integer_value": 37}, {"type": "HGVS, genomic, top level, other", "value": "NC_000020.11:g.25383511_25397601del14091insGG", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000020.10:g.25364147_25378237delinsGG", "integer_value": 37}, {"type": "HGVS, previous", "value": 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[{"assembly": "GRCh38", "chr": "20", "accession": "NC_000020.11", "start": 25294743, "stop": 25390835, "display_start": 25294743, "display_stop": 25390835, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "20", "accession": "NC_000020.10", "start": 25275378, "stop": 25371617, "display_start": 25275378, "display_stop": 25371617, "strand": "-", "variant_length": 96240, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "26090"}, {"db": "OMIM", "id": "613599", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:15868"}]}], "xrefs": [{"db": "dbVar", "id": "nssv3761628"}, {"db": "dbVar", "id": "nsv1067853"}, {"db": "OMIM", "id": "613599.0002", "type": "Allelic variant"}], "comments": [{"text": "The location of this deletion was determined from analysis of Fig. S4C in PubMed 20797687.", "type": "public", "datasource": "NCBI curation"}, {"text": "Deletion of exon 1 plus flanking sequences from ABHD12 (NG_028119.1), with insertion of GG", "type": "public", "datasource": "NCBI curation"}], "id": 15064}], "names": [{"value": {"type": "Preferred", "value": "NM_015600.4(ABHD12):c.-6898_191+7002delinsCC"}}], "id": 25}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "PHARC syndrome"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0012984"}]}, {"value": {"type": "Alternate", "value": "Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract"}, "xrefs": [{"db": "Genetic Alliance", "id": "Polyneuropathy%2C+hearing+loss%2C+ataxia%2C+retinitis+pigmentosa%2C+and+cataract/9132"}]}, {"value": {"type": "Alternate", "value": "Polyneuropathy-hearing loss-ataxia-retinitis pigmentosa-cataract syndrome"}, "xrefs": [{"db": "Orphanet", "id": "171848"}]}], "symbols": [{"value": {"type": "Alternate", "value": "PHARC"}, "xrefs": [{"db": "OMIM", "id": "612674", "type": "MIM"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0012984"}, {"db": "MedGen", "id": "C2675204"}, {"db": "Orphanet", "id": "171848"}, {"db": "OMIM", "id": "612674", "type": "MIM"}]}], "id": 17}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 57545}, "record_status": "current", "title": "NM_015600.4(ABHD12):c.-6898_191+7002delinsCC AND PHARC syndrome", "clinvar_assertions": [{"id": 20185, "submission_id": {"local_key": "613599.0002_POLYNEUROPATHY, HEARING LOSS, ATAXIA, RETINITIS PIGMENTOSA, AND CATARACT", "submitter": "OMIM", "title": "ABHD12, 14-KB DEL_POLYNEUROPATHY, HEARING LOSS, ATAXIA, RETINITIS PIGMENTOSA, AND CATARACT", "submitter_date": "2018-10-03"}, "clinvar_accession": {"acc": "SCV000020185", "version": 3, "type": "SCV", "date_updated": "2018-10-10", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2010-09-10"}], "external_ids": [{"db": "OMIM", "id": "613599.0002", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In 3 affected members of a family from the United Arab Emirates with polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC; 612674), Fiskerstrand et al. (2010) identified a homozygous 14-kb deletion and 2-bp insertion (del14007insGG) in the ABHD12 gene encompassing the promoter region and exon 1 of the gene. Two patients were in their twenties, and 1 was age 6 years. Common features included absent tendon reflexes, hearing loss, ataxia, cataracts; hearing loss occurred in childhood in all 3. Only the older 2 patients had retinitis pigmentosa."}, "citations": [{"ids": [{"source": "PubMed", "value": "20797687"}]}], "xrefs": [{"db": "OMIM", "id": "612674", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "ABHD12, 14-KB DEL"}}], "attributes": [{"type": "NonHGVS", "value": "14-KB DEL"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "ABHD12"}}]}], "xrefs": [{"db": "OMIM", "id": "613599.0002", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "POLYNEUROPATHY, HEARING LOSS, ATAXIA, RETINITIS PIGMENTOSA, AND CATARACT"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000000188", "version": 5, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "other", "date_last_evaluated": "1990-11-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a patient of Swedish/Danish extraction with gyrate atrophy of the choroid and retina (GACR; 258870), McClatchey et al. (1989, 1990) found deletion of 9 bp in the 3-prime splice site of IVS4, resulting in deletion of exon 5. The mutation was present in compound heterozygous state."}, "citations": [{"ids": [{"source": "PubMed", "value": "2220818"}], "type": "general"}, {"type": "general", "citation_text": "McClatchey, A. I., Kaufmann, D. L., Tobin, A. J., Shih, V. E., Berson, E. L., Gusella, J. F., Ramesh, V. Deletion in the OAT gene causes RNA splicing defect and results in gyrate atrophy. (Abstract) Am. J. Hum. Genet. 45: A206-only, 1989."}]}]}, {"sample": {"origin": "not provided", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided", "number_tested": 1}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000000165", "version": 1, "measures": [{"type": "deletion", "names": [{"value": {"type": "Preferred", "value": "NM_000274.4(OAT):c.425-4_429del"}}], "canonical_spdi": "NC_000010.11:124408632:CACTCCTATCA:CA", "attributes": [{"type": "FunctionalConsequence", "value": "exon loss", "xrefs": [{"db": "Variation Ontology", "id": "0381"}]}, {"type": "HGVS, coding, LRG", "value": "LRG_685t1:c.425_520del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001322974.2:c.-290-4_-286del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001171814.2:c.11-4_15del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001322971.2:c.200-3078_200-3070del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000274.4:c.425-4_429del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001322965.2:c.425-4_429del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001322966.2:c.425-4_429del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001322967.2:c.425-4_429del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001322968.2:c.425-4_429del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001322969.2:c.425-4_429del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001322970.2:c.425-4_429del"}, {"type": "HGVS, genomic, LRG", "value": "LRG_685:g.15310_15318del"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_008861.1:g.15310_15318del"}, {"type": "HGVS, genomic, top level", "value": "NC_000010.11:g.124408635_124408643del", "integer_value": 38}, {"type": "HGVS, genomic, top level, other", "value": "NC_000010.11:g.124408634_124408642del", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000010.10:g.126097204_126097212del", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_000274.3:c.425_520del"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein, RefSeq", "value": "NP_000265.1:p.Gly142_Ala173del"}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001322971.2:c.200-3078_200-3070del"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_000274.4:c.425-4_429del"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001171814.2:c.11-4_15del"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001322965.2:c.425-4_429del"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001322966.2:c.425-4_429del"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001322967.2:c.425-4_429del"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001322968.2:c.425-4_429del"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001322969.2:c.425-4_429del"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001322970.2:c.425-4_429del"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001322974.2:c.-290-4_-286del"}]}, {"type": "nucleotide change", "value": "EX5DEL"}], "cytogenic_locations": ["10q26.13"], "sequence_locations": [{"assembly": "GRCh38", "chr": "10", "accession": "NC_000010.11", "start": 124408633, "stop": 124408641, "display_start": 124408633, "display_stop": 124408641, "variant_length": 9, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 124408632, "reference_allele_vcf": "CCACTCCTAT", "alternate_allele_vcf": "C"}, {"assembly": "GRCh37", "chr": "10", "accession": "NC_000010.10", "start": 126097202, "stop": 126097210, "display_start": 126097202, "display_stop": 126097210, "variant_length": 9, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 126097201, "reference_allele_vcf": "CCACTCCTAT", "alternate_allele_vcf": "C"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "ornithine aminotransferase"}}], "symbols": [{"value": {"type": "Preferred", "value": "OAT"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "10", "accession": "NC_000010.11", "start": 124397303, "stop": 124418923, "display_start": 124397303, "display_stop": 124418923, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "10", "accession": "NC_000010.10", "start": 126085871, "stop": 126107544, "display_start": 126085871, "display_stop": 126107544, "strand": "-", "variant_length": 21674, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "4942"}, {"db": "OMIM", "id": "613349", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:8091"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "2220818"}], "type": "general"}], "xrefs": [{"db": "OMIM", "id": "613349.0022", "type": "Allelic variant"}, {"db": "dbSNP", "id": "386833609", "type": "rs"}], "comments": [{"text": "NCBI staff reviewed the sequence information reported in PubMed 2220818 Fig. 2 to determine the location of this allele on the current reference sequence.", "type": "public", "datasource": "NCBI curation"}, {"text": "9-bp deletion spanning 3'-acceptor of exon 4 causes skipping of exon 4 in NM_000274.3.", "type": "LocationOnGenomeAndProductNotAligned", "datasource": "NCBI curation"}], "id": 15204}], "names": [{"value": {"type": "Preferred", "value": "NM_000274.4(OAT):c.425-4_429del"}}], "xrefs": [{"db": "ClinGen", "id": "CA113968"}], "id": 165}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Ornithine aminotransferase deficiency"}, "xrefs": [{"db": "Genetic Alliance", "id": "Ornithine+aminotransferase+deficiency/5411"}, {"db": "MONDO", "id": "MONDO:0009796"}, {"db": "SNOMED CT", "id": "276426004"}]}, {"value": {"type": "Alternate", "value": "OAT deficiency"}}, {"value": {"type": "Alternate", "value": "Ornithine ketoacid aminotransferase deficiency"}}, {"value": {"type": "Alternate", "value": "Gyrate atrophy"}}, {"value": {"type": "Alternate", "value": "OKT deficiency"}}, {"value": {"type": "Alternate", "value": "Hyperornithinemia with gyrate atrophy of choroid and retina"}}, {"value": {"type": "Alternate", "value": "Girate atrophy of the retina"}}, {"value": {"type": "Alternate", "value": "Gyrate atrophy of choroid and retina"}}], "symbols": [{"value": {"type": "Preferred", "value": "GACR"}, "xrefs": [{"db": "OMIM", "id": "258870", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "HOGA"}, "xrefs": [{"db": "OMIM", "id": "258870", "type": "MIM"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0009796"}, {"db": "MedGen", "id": "C0018425"}, {"db": "Orphanet", "id": "414"}, {"db": "OMIM", "id": "258870", "type": "MIM"}]}], "id": 59}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 57691}, "record_status": "current", "replaces": ["RCV000049536"], "title": "NM_000274.4(OAT):c.425-4_429del AND Ornithine aminotransferase deficiency", "clinvar_assertions": [{"id": 20331, "submission_id": {"local_key": "613349.0022_GYRATE ATROPHY OF CHOROID AND RETINA", "submitter": "OMIM", "title": "OAT, EX5DEL_GYRATE ATROPHY OF CHOROID AND RETINA", "submitter_date": "2018-02-01"}, "clinvar_accession": {"acc": "SCV000020331", "version": 2, "type": "SCV", "date_updated": "2018-02-04", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "1990-11-01"}], "external_ids": [{"db": "OMIM", "id": "613349.0022", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a patient of Swedish/Danish extraction with gyrate atrophy of the choroid and retina (GACR; 258870), McClatchey et al. (1989, 1990) found deletion of 9 bp in the 3-prime splice site of IVS4, resulting in deletion of exon 5. The mutation was present in compound heterozygous state."}, "citations": [{"citation_text": "McClatchey, A. I., Kaufmann, D. L., Tobin, A. J., Shih, V. E., Berson, E. L., Gusella, J. F., Ramesh, V. Deletion in the OAT gene causes RNA splicing defect and results in gyrate atrophy. (Abstract) Am. J. Hum. Genet. 45: A206-only, 1989."}, {"ids": [{"source": "PubMed", "value": "2220818"}]}], "xrefs": [{"db": "OMIM", "id": "258870", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "OAT, EX5DEL"}}], "attributes": [{"type": "NonHGVS", "value": "EX5DEL"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "OAT"}}]}], "xrefs": [{"db": "OMIM", "id": "613349.0022", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "GYRATE ATROPHY OF CHOROID AND RETINA"}}]}]}}, {"id": 131331, "submission_id": {"local_key": "FINDIS870", "submitter": "Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)", "submitter_date": "2013-05-19"}, "clinvar_accession": {"acc": "SCV000081973", "version": 1, "type": "SCV", "date_updated": "2013-07-24", "date_created": "2013-07-24", "org_id": "500116", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["other"], "comments": [{"text": "Converted during submission to Likely pathogenic.", "type": "ConvertedByNCBI"}]}], "observed_in": [{"sample": {"origin": "not provided", "species": {"value": "human"}, "affected_status": "not provided", "number_tested": 1}, "methods": ["not provided"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_000274.3:c.425-5_428del"}], "citations": [{"ids": [{"source": "PubMed", "value": "2220818"}], "type": "general"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "Ornithine aminotransferase deficiency"}}], "xrefs": [{"db": "OMIM", "id": "258870", "type": "MIM"}]}]}, "comments": [{"text": "FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference", "type": "public"}]}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000000713", "version": 3, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "1998-04-24"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Berg et al. (1994) detected a heterozygous T-to-C transition in the putative promoter region of the PROC gene in a patient with type I protein C deficiency and a history of recurrent venous thrombosis (THPH3; 176860). The mutation occurred 14 bp upstream of the transcription initiation site and within a sequence strongly homologous to the consensus binding site for a liver-enriched transcription factor, hepatocyte nuclear factor-1 (HNF1; 142410). Transfection experiments demonstrated that a CAT reporter gene construct containing 626 bp of the putative PROC gene promoter was capable of driving CAT expression in hepatoma cells. Levels of CAT expression from constructs bearing the mutation were found to be drastically reduced by comparison with the wildtype, consistent with the reduced plasma protein C antigen levels observed in the patient. The findings indicated a vital role for HNF1 in the expression of the PROC gene in vivo."}, "citations": [{"ids": [{"source": "PubMed", "value": "7881411"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "Spek et al. (1998) found that the region around the -14T-C mutation corresponds to a binding site for the transcription factor HNF6 (ONECUT1; 604164), and that this site completely overlaps an HNF1-binding site. In vitro studies showed that HNF6 and HNF1 bound in a mutually exclusive manner. In transient transfection experiments, both HNF6 and HNF1 transactivated the wildtype PROC promoter, and the mutant promoter abolished transactivation by HNF6. Deletion studies showed that HNF1 activity was regulated by sequences either upstream or downstream of the HNF6/HNF1 site. Spek et al. (1998) concluded that HNF6 is the major determinant of protein C gene activity."}, "citations": [{"ids": [{"source": "PubMed", "value": "9553065"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000000678", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NG_016323.1:g.5006T>C"}}], "canonical_spdi": "NC_000002.12:127418424:T:C", "attributes": [{"type": "HGVS, genomic, LRG", "value": "LRG_599:g.5006T>C"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_016323.1:g.5006T>C"}, {"type": "HGVS, genomic, top level", "value": "NC_000002.12:g.127418425T>C", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000002.11:g.128176001T>C", "integer_value": 37}, {"type": "HGVS, protein"}, {"type": "nucleotide change", "value": "-14T-C"}], "cytogenic_locations": ["2q14.3"], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 127418425, 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"names": [{"value": {"type": "Preferred", "value": "Thrombophilia due to protein C deficiency, autosomal dominant"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0008316"}]}, {"value": {"type": "Alternate", "value": "PROC DEFICIENCY, AUTOSOMAL DOMINANT"}, "xrefs": [{"db": "OMIM", "id": "176860", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT"}, "xrefs": [{"db": "OMIM", "id": "176860", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Thrombophilia, hereditary, due to protein C deficiency, autosomal dominant"}, "xrefs": [{"db": "Genetic Alliance", "id": "Thrombophilia%2C+hereditary%2C+due+to+protein+c+deficiency%2C+autosomal+dominant/9396"}]}], "symbols": [{"value": {"type": "Alternate", "value": "THPH3"}, "xrefs": [{"db": "OMIM", "id": "176860", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "PCD"}, "xrefs": [{"db": "Genetic Testing Registry (GTR)", "id": "GTR000503185"}]}], "attributes": [{"value": {"type": "disease mechanism", "value": "loss of function"}, "xrefs": [{"db": "Genetic Testing Registry (GTR)", "id": "GTR000202257"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000320550"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000503185"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000512308"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000515785"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000521658"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000523364"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000576178"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0008316"}, {"db": "MedGen", "id": "C2674321"}, {"db": "Orphanet", "id": "745"}, {"db": "OMIM", "id": "176860", "type": "MIM"}]}], "id": 170}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 58216}, "record_status": "current", "title": "NG_016323.1:g.5006T>C AND Thrombophilia due to protein C deficiency, autosomal dominant", "clinvar_assertions": [{"id": 20863, "submission_id": {"local_key": "612283.0023_THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT", "submitter": "OMIM", "title": "PROC, -14T-C_THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT", "submitter_date": "2015-08-19"}, "clinvar_accession": {"acc": "SCV000020863", "version": 2, "type": "SCV", "date_updated": "2015-08-21", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "1998-04-24"}], "external_ids": [{"db": "OMIM", "id": "612283.0023", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Berg et al. (1994) detected a heterozygous T-to-C transition in the putative promoter region of the PROC gene in a patient with type I protein C deficiency and a history of recurrent venous thrombosis (THPH3; 176860). The mutation occurred 14 bp upstream of the transcription initiation site and within a sequence strongly homologous to the consensus binding site for a liver-enriched transcription factor, hepatocyte nuclear factor-1 (HNF1; 142410). Transfection experiments demonstrated that a CAT reporter gene construct containing 626 bp of the putative PROC gene promoter was capable of driving CAT expression in hepatoma cells. Levels of CAT expression from constructs bearing the mutation were found to be drastically reduced by comparison with the wildtype, consistent with the reduced plasma protein C antigen levels observed in the patient. 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Deletion of the second allele was present in affected members of each family."}, "citations": [{"ids": [{"source": "PubMed", "value": "9537412"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000004442", "version": 1, "measures": [{"type": "microsatellite", "names": [{"value": {"type": "Preferred", "value": "NM_004937.3(CTNS):c.60_61del (p.Cys20_Glu21delinsTer)"}}], "canonical_spdi": "NC_000017.11:3640263:TGTG:TG", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001374495.1:c.-220TG[1]"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001374496.1:c.-296+2950_-296+2951del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001374493.1:c.-299TG[1]"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001374494.1:c.-381+2950_-381+2951del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001031681.3:c.60_61del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001374492.1:c.60_61del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_004937.3:c.60_61del"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_052852.1:g.1056CA[1]"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_012489.2:g.8797TG[1]"}, {"type": "HGVS, genomic, top level", "value": "NC_000017.11:g.3640264TG[1]", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000017.10:g.3543558TG[1]", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_004937.2:c.60_61del"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001026851.2:p.Cys20_Glu21delinsTer"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001361421.1:p.Cys20_Glu21delinsTer"}, {"type": "HGVS, protein, RefSeq", "value": "NP_004928.2:p.Cys20_Glu21delinsTer"}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001374493.1:c.-299TG[1]"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001374495.1:c.-220TG[1]"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001374494.1:c.-381+2950_-381+2951del"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001374496.1:c.-296+2950_-296+2951del"}]}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_001031681.3:c.60_61del"}]}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_001374492.1:c.60_61del"}]}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_004937.3:c.60_61del"}]}], "cytogenic_locations": ["17p13.2"], "sequence_locations": [{"assembly": "GRCh38", "chr": "17", "accession": "NC_000017.11", "start": 3640264, "stop": 3640265, "display_start": 3640264, "display_stop": 3640265, "variant_length": 2, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 3640263, "reference_allele_vcf": "ATG", "alternate_allele_vcf": "A"}, {"assembly": "GRCh37", "chr": "17", "accession": "NC_000017.10", "start": 3543558, "stop": 3543559, "display_start": 3543558, "display_stop": 3543559, "variant_length": 2, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 3543557, "reference_allele_vcf": "ATG", "alternate_allele_vcf": "A"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "cystinosin, lysosomal cystine transporter"}}], "symbols": [{"value": {"type": "Preferred", "value": "CTNS"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "17", "accession": "NC_000017.11", "start": 3636459, "stop": 3663103, "display_start": 3636459, "display_stop": 3663103, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "17", "accession": "NC_000017.10", "start": 3539761, "stop": 3566396, "display_start": 3539761, "display_stop": 3566396, "strand": "+", "variant_length": 26636, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "1497"}, {"db": "OMIM", "id": "606272", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:2518"}]}], "xrefs": [{"db": "OMIM", "id": "606272.0002", "type": "Allelic variant"}, {"db": "dbSNP", "id": "1567695026", "type": "rs"}], "comments": [{"text": "ClinGen staff contributed the HGVS expression for this variant.", "type": "public", "datasource": "ClinGen"}], "id": 19481}], "names": [{"value": {"type": "Preferred", "value": "NM_004937.3(CTNS):c.60_61del (p.Cys20_Glu21delinsTer)"}}], "id": 4442}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Nephropathic cystinosis"}, "xrefs": [{"db": "GeneTests", "id": "54105"}, {"db": "Genetic Alliance", "id": "Nephropathic+cystinosis/5143"}, {"db": "MONDO", "id": "MONDO:0100151"}]}, {"value": {"type": "Alternate", "value": "Lysosomal cystine transport protein, defect of"}}, {"value": {"type": "Alternate", "value": "Cystinosin, defect of"}}, {"value": {"type": "Alternate", "value": "Abderhalden Lignac Kaufmann disease"}}, {"value": {"type": "Alternate", "value": "Abderhalden-Kaufmann-Lignac syndrome"}}], "symbols": [{"value": {"type": "Preferred", "value": "CTNS"}, "xrefs": [{"db": "Genetic Testing Registry (GTR)", "id": "GTR000529128"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000558532"}, {"db": "OMIM", "id": "219800", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "Cystinosis comprises three allelic phenotypes: Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life. Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years. The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1400"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "10074"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301574"}, {"source": "BookShelf", "value": "NBK1400"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0100151"}, {"db": "MedGen", "id": "C2931187"}, {"db": "Orphanet", "id": "213"}, {"db": "Orphanet", "id": "411629"}, {"db": "OMIM", "id": "219800", "type": "MIM"}]}], "id": 1222}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 62195}, "record_status": "current", "title": "NM_004937.3(CTNS):c.60_61del (p.Cys20_Glu21delinsTer) AND Nephropathic cystinosis", "clinvar_assertions": [{"id": 24867, "submission_id": {"local_key": "606272.0002_CYSTINOSIS, NEPHROPATHIC", "submitter": "OMIM", "title": "CTNS, 2-BP DEL, 397TG_CYSTINOSIS, NEPHROPATHIC", "submitter_date": "2017-08-23"}, "clinvar_accession": {"acc": "SCV000024867", "version": 2, "type": "SCV", "date_updated": "2017-08-27", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "1998-04-01"}], "external_ids": [{"db": "OMIM", "id": "606272.0002", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In 2 families from central France, Town et al. (1998) found that nephropathic cystinosis (219800) was associated with hemizygosity for the same 2-bp deletion of the CTNS gene: deletion of TG at 397/399 resulted in a stop codon at the site of the mutation. The 2 families shared a common haplotype that segregated with the deletion. Deletion of the second allele was present in affected members of each family."}, "citations": [{"ids": [{"source": "PubMed", "value": "9537412"}]}], "xrefs": [{"db": "OMIM", "id": "219800", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "CTNS, 2-BP DEL, 397TG"}}], "attributes": [{"type": "NonHGVS", "value": "2-BP DEL, 397TG"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "CTNS"}}]}], "xrefs": [{"db": "OMIM", "id": "606272.0002", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "CYSTINOSIS, NEPHROPATHIC"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000006747", "version": 6, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2006-07-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Kotzot et al. (1994) described an inbred Turkish family in which a boy and a girl related as first cousins, and in each case the offspring of consanguineous parents, had tyrosinase-positive oculocutaneous albinism, recurrent bacterial infections, granulocytopenia, intermittent thrombocytopenia, microcephaly, protruding midface, rough and projecting hair, and mild mental retardation (HPS2; 608233). Using genetic linkage analysis and targeted gene sequencing, Jung et al. (2006) defined a homozygous genomic deletion in AP3B1. The mutation led to in-frame skipping of exon 15 and thus perturbed proper assembly of the heterotetrameric AP3 complex. Despite distinct ultramorphologic changes suggestive of aberrant vesicular maturation, no functional aberrations were detected in neutrophil granulocytes. However, a comprehensive immunologic assessment revealed that natural killer (NK) and NKT-cell numbers were reduced in the AP3-deficient patients. The findings extended the clinical and molecular phenotype of human AP3 deficiency and provided insight into the role of the AP3 complex for the innate immune system. The deleted interval spanned 8,168 bp, including a large part of intron 14, the complete exon 15, and a small part of intron 15. Loss of exon 15 resulted in the absence of amino acid 49 to 550 while preserving the reading frame."}, "citations": [{"ids": [{"source": "PubMed", "value": "16537806"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": "8042664"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000006375", "version": 4, "measures": [{"type": "deletion", "names": [{"value": {"type": "Preferred", "value": "NM_003664.5(AP3B1):c.1474-7072_1650+921del"}}], "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001271769.2:c.1327-7072_1503+921del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_003664.5:c.1474-7072_1650+921del"}, {"type": "HGVS, genomic, LRG", "value": "LRG_170:g.151314_159483del"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_007268.1:g.151314_159483del"}, {"type": "HGVS, genomic, top level", "value": "NC_000005.10:g.78140222_78148391del", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000005.9:g.77436046_77444215del", "integer_value": 37}, {"type": "HGVS, protein"}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001271769.2:c.1327-7072_1503+921del"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_003664.5:c.1474-7072_1650+921del"}]}, {"type": "MolecularConsequence", "value": "splice donor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001575"}, {"db": "RefSeq", "id": "NM_001271769.2:c.1327-7072_1503+921del"}]}, {"type": "MolecularConsequence", "value": "splice donor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001575"}, {"db": "RefSeq", "id": "NM_003664.5:c.1474-7072_1650+921del"}]}, {"type": "nucleotide change", "value": "EX15DEL"}], "cytogenic_locations": ["5q14.1"], "sequence_locations": [{"assembly": "GRCh38", "chr": "5", "accession": "NC_000005.10", "start": 78140222, "stop": 78148391, "display_start": 78140222, "display_stop": 78148391, "variant_length": 8170, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 78140221, "reference_allele_vcf": "TGCAAATCTGGTAAATTATACTACTATTAAAAGTGGTTTCCCTTTCCTCTGCAGGACAAGGTCCATACTACTTAGCAGAGCATACAAGCCACTCCATGCGTTCAAACTGCAAAATGTCTTAGTCCATTTGGGCTACTGTTAGAAAATACCATAAACTGGGAAGCCTATTAATAATATAATTAATAATAAAAATTTATTTCTCACAGTTCTGGAGGCTGGGAAATCCAAGATCAAGGTACCCACAGTTCTGGTGTCTAGTGAGCACCCATTTTCTAATTTACAGATAGCACCTTCTCACTGTGTCCTCACATGGCAGAAGCAGCAAGCTAGCTCTCAGGGATCTCTTTTCTAAGAGCATAAAGTTCATTTATAAAGGCTCCACCCTTATGACCTAATCACCTCCCAAAGGTCCTACCTCCTAATACCATCACATGGGTGATCAGGTTTCACCACATGAACTTTGGGGGATATAAACTTTCAGACCATTGTACCTGCCATTCTGGACTCACCTTCAAAAAGTTTCCCAGAAACACCAAGCTGTTTCTTGACTCTGACCCTGTGCTTTCCTCTTTCTGTACAGTAAACCACTCTTACAAGCCCTTAGTCAAGAGTTTCATCCTTTATAAAATTTTCTCTGACCTCACATCGACTTCAGACTTTATAATTCGTCTAGAATTCCACTGTATGTCAATACTTCTGCTACAGCATTAACACACACTATTTCATTTTTTAATCTGTTTTCTCTCTTACTAGACTAGAATGTCATCTGTTTGCACTAGTATCATCTAACATAGAACCTGAAACAAACAGGCACCTAGAAATTGTTGAATGGTCAGACTAATGAAGGCACAGACCCCCGCTGTTTGATCAGAGTGAAGAGGAAAGTACGTATTAGATAGGTTGACTAACATTTGCCTCTCACCTGTTTGGAGTTGGTTAAATACAATTTTGCTCCCAGATTTAATATCTGCAGTTTTACCAGATCATCTTCACTAGTGAAGCTTTTAGCCATCTTCCTCAAAACATCAGGGGCAATTTTAGGAACTCGTTCACAGTTTTCTCCAATTAGCCAAAGAATACTTGCTCTAGCAACAGGAACCTAATATGAGAAGCAGATTACATAGTTAGAAGTAAGTTAATCATACTCTAATATTAACATAGAAAAGGTTTTAACTATTACAAAAGTTTTACAGCTATTAATTAATTTAATGTATATCTAGGAATTAATCCTGTATTTATGAATTTTCGTCAGTTATCAAAAAATAAACACATAGGAAATCTCATTAAAATTGATTTCGAAGAGAATATCTTAGAAAATATTCATACAGCAAAAACCGATGGTCTAGAATCTAGATTCTATCAGAGACGAACAAATTCTAGAAGCCAGTCTAGCTGCCCATACCTATTTGTTTCTCCATTATCTGTTGCTGCTTTTGTGCTATAATGGCAGAAATAGTTACAGTGAAGACCATATGGTCCTCAAAGCCAAAAATATTGACTGTCTAGCAATTTATAGAAATGGTTTGCTGACCCCTGCTCTAGAACAGCAGTTCCCAAACCTCAATGCCCACAAAAATCATCCAGGGTTCTTACTAAAAAGACAGGTCCTGGGATCAGCTCCAAAATAGTATTTCTGTGGTGGGGCCCAGAAATCTATGTTTTAATTTAAAAAGCATCACAGATGACTCCTGAGACAGGTGGTCCACAAAGCCCATTTGAGAACCCACAGATAATACAGAAAAAGAAACAGATCAATTAGGTACTATGATTCCAAATCAAAACTGTTTTTGCTCTTTATGTATTAGCATCTACAACACTGGAAATATATCAAACTGATAAGATCATCAAGGTCTGCTTATAAAATCATGAATCCCAGTCTATTATTTGGTCAACAAAAGAAACAGGGATAAATTTGTCCAATATTGCATTTTGGCACTATATTTTTAAATAAACTGCATTTCAATATAATTTATGTTCTTAAAAGTCACTGCTTTGTGACAAATTGGAAACCTTCCATCAGTACCATTAAGACCAACAATTTAGAGTATGCAAATTAGTTTTATTACTATTTGCTTATTTGCATCCTCCCCTATTCCAAAAGGAATTTGAGAGGGTGTGTAAATTCATTTCAGTGAACATTTTCACCTCGCACAGAAAATTTGTTTTTTATAATAAGTGAAAAGGCTGACAGCTATCATTAAAAGGTGGCATCACGAGGAAAGATAATGTTCTTTTTATGAAGTCCTTTTACAATTTCTCAAAGTCCTAATATTTTCTGTAGTTTCATGGCTATACATAGTAGGATTGTTAAAGAAAAAAGTGAGAATAAGGACCTTTCCATAGCTAAAATTTTATCACAATATCTACCATTGCAAAATCTTTCAAAACACCCACATTATGAAATTATATAAAAATATTAAGTTACAATATTGAGTCCTTCACTAGAATCAGAATGAGATGATCAAAAAAGCTTTTAAATAAAAAGGTATATATTTTAAAACAGTGTAACAGCATGTCTTTAAATTATTATTTAGCATGTTTGGTGAGACACAAGAAATCCATATACTTGTGCAATTAGAAAAAGGTCTAAGTGCTATTAAAAATCTATTCATGCAGTGTGATAAAACTGATGCCCTTACTGCATACTGATTTCTGGAAAGAAAAGAGGTTATTTCTAACGTTCCAAAGGTTACACTGCATTAAGACCTTACTCCCAATCTATTATTTTAAATTGGGCTAAAGAATAGTAATTGAGTGGTACATTAAATTTTCCAGTATAGAGGAATTCAAGTTGCCTGCCATAATGAAAGGTAGTTCTAAATAAGAATATATGTGCAACTTCAAATTTCAGTTATGCTAGATTTATTTTTCTTAAATATTTTATTATATATTGCTAGTATAAAAATCAGAATTCTATGACATACCATAATCTATTATCCCATTTTAAGTAATTTTCTTCTGGTAACAATCTTTTGCAATTAAAAAGACGATCCCAAAAACAAGTAATGTTTAAAGAGATTGTTTATATTCATGAATATACTAAAATTAAAATTAAAATATTGGAATACTGTAAACACTCACGATACATATATTTAAAATACAACTCTTTGAAAAAATTAAAAATCAATAAATCACAATGCTCACAATAAAAATCTCAAGATGGTGGTGAGAATAAGATTTGTAGTTTTCTAGAACTGAGCTAATAAAATCCCCAAGAATTTTTAAAACTTAGAAAACTTCACCACAAGAAATAATATCAATATAAATATACCAAACTTTTGGTGATGGCATTGTATTACAAAGCTTAGGAAACTGACAAAGACAACATTTTTGAGCAGGTGGATGGGATCAGAATACTAAGATTTTTGGATTCCAGCTTTCCCTTTCTCTTCCCATTAAGCAACAGGACTCTCATTTATACACCATTGACACTATGAATTCACAGCCACTACTTTCAAAGATTTGAAGCACCTGAAAAAAAGGCAAGTAAGAAAATTAGTCACTTTTTAGAGGCCAGGCACAGTGGCTCATGCCTAAAATCCCAGCACTTTGGGAGGCTGAGGCGGGTGGATCACTTGAGGACAGGAGTTTGAGACCAGCCTGGCCAACATGGTGATACCCTGTCTCTACTAAATATACAAAATTAGCCTGGCACACTCCTGTAATTCCAGCTACTTGGGAGGCTAAGGTAAAAGAATCACTTGAACTCAGGAGGCAGAGGTTGCAGTGAGCTAAGATTGTGCCACTGCACTCCAGCCTGGGTGACAGAGCGAGACTCTGTCTCAAAAAAAAAAGAAAAGTAAATTAGTCACTTTTTGTTCCCCATGGTCTTTTTAACCACAAAATAAATAGGAACACTGAAATAAAACCAAACTAATAATACACACACAGACACAGACACAGGTACAGACACACACACAGAGTCATACATATGATATAATACTTTCATTATGAAGCTCTGCTTTTCAATATTCTCAAAGACAAATTGGATTGTAAATGACTTTGCCTGATTCTTTATTCTAAATGCCCTGAGAAAGTGATTAAATGCACTTTTCAAACCTTGTACTAGAAGGCAGTTTCCACGGCCACCACAACCCATTAATTTGCCAGCAAAAACAAATAATGATTCCTAGCTCACCACAGCAGCTATAGAAAGACATCTAGAAAGATTTTGCAGATCACTCTGTAAGCAGTTCAATTTAAAAGCTATTGTGTTTCAACACCAGCCCACTGCACAGTGCAACAGTCCAAAGTAAACCCTACAAAAACATCAATTTCATTTATTTAAATTTGTCAAAGGCAAAATCAGTAGACATCTAAGCAAACTGCATACCAACAGCAAATCAGATCTAATACTCTGTATCTGGACTCAATATGCATTAAAGCCTAAGCCTGAATTACAATGGGGTGCCAGAGAAAGGGTGGGTAACTTGTGAAATGGCAGGCATCCTGTGAGGCATCTGGGCAACAAGGATACAAAGTGCTATTTCAATATTACTCAGTTTTTACAGAATAACATCTTTCAGTTGTTAAGATATGAAATCCCATCTGTCCCATTAAACATTATGTGAAATCCTGTCAGAGCAATCCACAGGTAGTATGGGTTGTTTTGTTGTTGTTGTTGTTTTTTAAAGACAGGGTCTTACTCTGTCATCCAGGCTGGAGTGCGGTGGTGCAATCATTGCTCACTACAACCTCAAACTCCTGGGCTCAAGCAATCCTCCCGCCTCAGCCTCCCAAAGTTCTGGGATTACAGGCATGAGCCACCATGCCAGCTGATAGTATGCATTTTATTCTAGAAGAACTCCAAAACCAGTATTTATCATAAATGAAGGATACGCCAAAGGACAGAATACTCACAATCAGAACATGTAAGTTGACTGTATTACAGACATAAATCTATTTGATTTGACCGAATTCAAAATGTAAAATACATTTAAACTTTAGTTTTTATATTTTCAATTATTACTAAATAACCAATTAAAACAAAGCCCTCAATATGATAAAATCTATGTTCTCTTTTTAAAACAAATTACATAGCTAATATCTATTGAGCTCTTACCATGTGCCATGCACTGTTTTTGAGAGCTTTACGTATTTTCTCAGTCATTCATCGCCAAAGCCCTATGAAGTATGCTCTACTATGATCTGCACTAGACATATGAGGAAACTAGGTAACAAATGAGTTAAGAAACTTGCCCACATCTCACAGCTGGTTAGTGGTGGAACTAGGATCAGAACTCCAAATCTGAATCCAAAATTCATACTGGATCACTGGGTAGCGACAAAATGAGTGTGGTAAACTAGGAAGAATACTGGTCAGCAAGCTGTTGAGACCGGTTCTGATCCCACACTGATGGTGTTACATCAAGGAGGCAATTAACTTCACCTCACTGGGGTCATATTTACTTATTAATCAGATGAAGGATTATTCCTTCATCCTCTGTTTGTCTGCCACATTGTGCAATGGCTCCCTTAGTGCCTCCTGCCATTTCCCCAAGAGCCAGATTTTCAGGGCAGACCCAGGCCATCCTCTTGCCTGTTCCCACACCCGTGTATAGTGGGACATTTTCCCACTTCTTTCACCTCTTCTTTTAAGGATAGGTAAGGTGGCCAGGTGGGAAGAGGTCTTGCTATCACTTCTGTTCTCTCTCCTTCCAGAAGAAAGATGGACCCAGGATTCTGCCCTAATAAAGTGGCTCAGGCACTGAAGGAAAACATGCTCAATATTGACCCATTGTCCTTAGATATTGGACAGACTGGCTTTTCCTAAAATTGCAGTGTTTTAGAATGACACTCCTGGGTTTGATGGTGAAATAGGTAGAGATTCAGGAGGACAGAAGTCTCATTTAAGGCTCTTATTTTAAGGCTCACATTTTAAAATCACTTGCCTACGTTTAGGAGTTATCAGGTACTTGGTCGGATTAATAAAACACTGCTTTTATTTCCACATGGCCATTGTTCTTGTATAAACAGCTCTCCTGACTGGAACAGAGAGATTCTGGGGATTCAATCATTCTTCTTTCCTGACTTTGAAGTTATGTCTGCTACATCCCTCATCACCTTCTCCTGGGGTAACTTGTGGTTGACCATTTTGAGGGTTCTGCACAACAAATTGTTTTGATTCTTCCTTGCTTGTCCCACCTTCAAGCACTTCAGTTTCCTCAGATACGTTAGATGAGCAGTAACAACTAATTATCAGCTTTTCATTCTCCTTAAGTTCAAATGTGTGCTGTAGAATTCCATACAGCTTTCTTGTATTTTAATTTCTTTTATTATCATATTCCAGATTTGTCTACTTTTGTTACCTCTCTCTGCTTCATAATAATTAGAAGGGAATTTTGTTTTATTTTCTTTCCAAAAGACCAGATTTAACATGTACTTTTCAACTCATATATATTTTTTGTATTCTATTTTACAAAATCAGCATTGATCCCTCTTCTGTTTTGATTCGTTTTTCTTTTATTTTATATCCCTATACTTTAAAAATGGTGATCTTTATAACTTTAGCCATGTCCTACATGTTTTGAAATAAAGCATTTTATTTCCTGGGTTTTAGAAAAAAGTTTGCATTTCTTCTTTAAATGCATTCTTTAATCTGAAAGTACATTTCTTACTTTACAACTGGTCTGGTACCCTTTTAAATTATTTAAGTCTCATTTCATTGCTTAAGGTCAAAGAATGCAAAATCTTTAAGCTTCCTTTATGCCTAAATACATTCTTGATTTTTTGAAAATATTCACTGGATATACTCCTAAAAGTGGGTATTATCTGTTCAAGAGATATAAGGTTTTAGCTATATTTACTAAATAAGTTTTTGATTACTTAATTTTCTTACTTATATCTGTCTACTAGAAATATCTAATATGAGAGAAATACATTACAGTCACACATTGTAACTATTTTATCAATTTCTCCTCACATTTTGAATAGATTTTTCCTTTACATATTTATTTGGTTGCCATATTTTTTGTGCAAATAGGTTTGTGCTTATTACTTTCTTTACAAATTACCCTTTTTTCATTTTATAATGTTCCTTTTTATCTTGTTAAATGCTTTTAATTAACTGTAAATCTCACTTTCTTGTTCATATTTGCTTAATATCTCTTTCCTTACCTTCTTATTTTCAACTTTTATCACTTGATTAAGGTGCTTTAACTATAAATGGCCTGTAGCTAGTTTTTGTTTTTATTCCAATTTGTAAGTCTGTCTTTTGATGAGAAAATTCAGTCCATTCATATTCAAGATGAGAAATATTTGATTTTATTTCTTCCATCTTTATTACTTTTAAATACTTATTATTTATTTTACATTTGTTTTCTTTCTTTCTTATTTTTTTTCTGGCTTTGTAAAACTGCTATTTGTTCCTTTATTTTCCTTTGTGAATACTGAATTCTCACCATATTTTTGTATCTATTAATGGTTATCTTCTGAGAAAAACAAAAGCTGAAAAAAATAAGCTTTGCTATATAGAGCTGTAAGACTGTACTTATTTGGCTTATAGTCCAGCAACTGTTGAGAAAGTTGATGCATCAGCCAGGTGCCATGGCTCACGCCTGTAATCCCAGCACTTCGGGAGGCTGGGGTGAGATCACCTGAGGTCAGGAGTTTGAGACCAGCGTGGTCAACATGGGGAAACCCCATCTCTACTAAAAACACAAAAATTATCCAGGCACGGTGGCGCATGCCTGTAATCCCAACTACTCAGAGGCTGAGGCAGGAGAATCACTTGAACCTGGGAGGTGGAGGTTGCAGTGAGATGAGATTGCGCCACTGCACTCCAGCCAGGGTGACAGAGCAAGACTCCATTAAAAAAAAAAAGGGAAAGAGAGAGAATGAGCGAGAAAAAGAAAGTTTACACATCAAAAGTATCTTCTGTATCCCTGGACATGAATATACTCAAATAGAAGAAAGTTTTCTTCCAAGAAAGCCTAGGGTTTGCCAGATACAGGCCTCATACACTGTTACAGGTTTTATGTATAGCAGCTGCACTCTCCTGAAGCCCTAGTACTTATAATTGCCTCTTCCTTTCTAAACAGGACCAGAACGAGTTTACTAGCACAAGTTTTAACTAAATTTTGCACAAGAAGTCTGGGGAGATACAGAACTCCTAGTTCCTTCTCATAATCAGATACATACTTCTCTACCATTACCTGTAAACAAGGTATTAA", "alternate_allele_vcf": "T"}, {"assembly": "GRCh37", "chr": "5", "accession": "NC_000005.9", "start": 77436046, "stop": 77444215, "display_start": 77436046, "display_stop": 77444215, "variant_length": 8170, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 77436045, "reference_allele_vcf": "TGCAAATCTGGTAAATTATACTACTATTAAAAGTGGTTTCCCTTTCCTCTGCAGGACAAGGTCCATACTACTTAGCAGAGCATACAAGCCACTCCATGCGTTCAAACTGCAAAATGTCTTAGTCCATTTGGGCTACTGTTAGAAAATACCATAAACTGGGAAGCCTATTAATAATATAATTAATAATAAAAATTTATTTCTCACAGTTCTGGAGGCTGGGAAATCCAAGATCAAGGTACCCACAGTTCTGGTGTCTAGTGAGCACCCATTTTCTAATTTACAGATAGCACCTTCTCACTGTGTCCTCACATGGCAGAAGCAGCAAGCTAGCTCTCAGGGATCTCTTTTCTAAGAGCATAAAGTTCATTTATAAAGGCTCCACCCTTATGACCTAATCACCTCCCAAAGGTCCTACCTCCTAATACCATCACATGGGTGATCAGGTTTCACCACATGAACTTTGGGGGATATAAACTTTCAGACCATTGTACCTGCCATTCTGGACTCACCTTCAAAAAGTTTCCCAGAAACACCAAGCTGTTTCTTGACTCTGACCCTGTGCTTTCCTCTTTCTGTACAGTAAACCACTCTTACAAGCCCTTAGTCAAGAGTTTCATCCTTTATAAAATTTTCTCTGACCTCACATCGACTTCAGACTTTATAATTCGTCTAGAATTCCACTGTATGTCAATACTTCTGCTACAGCATTAACACACACTATTTCATTTTTTAATCTGTTTTCTCTCTTACTAGACTAGAATGTCATCTGTTTGCACTAGTATCATCTAACATAGAACCTGAAACAAACAGGCACCTAGAAATTGTTGAATGGTCAGACTAATGAAGGCACAGACCCCCGCTGTTTGATCAGAGTGAAGAGGAAAGTACGTATTAGATAGGTTGACTAACATTTGCCTCTCACCTGTTTGGAGTTGGTTAAATACAATTTTGCTCCCAGATTTAATATCTGCAGTTTTACCAGATCATCTTCACTAGTGAAGCTTTTAGCCATCTTCCTCAAAACATCAGGGGCAATTTTAGGAACTCGTTCACAGTTTTCTCCAATTAGCCAAAGAATACTTGCTCTAGCAACAGGAACCTAATATGAGAAGCAGATTACATAGTTAGAAGTAAGTTAATCATACTCTAATATTAACATAGAAAAGGTTTTAACTATTACAAAAGTTTTACAGCTATTAATTAATTTAATGTATATCTAGGAATTAATCCTGTATTTATGAATTTTCGTCAGTTATCAAAAAATAAACACATAGGAAATCTCATTAAAATTGATTTCGAAGAGAATATCTTAGAAAATATTCATACAGCAAAAACCGATGGTCTAGAATCTAGATTCTATCAGAGACGAACAAATTCTAGAAGCCAGTCTAGCTGCCCATACCTATTTGTTTCTCCATTATCTGTTGCTGCTTTTGTGCTATAATGGCAGAAATAGTTACAGTGAAGACCATATGGTCCTCAAAGCCAAAAATATTGACTGTCTAGCAATTTATAGAAATGGTTTGCTGACCCCTGCTCTAGAACAGCAGTTCCCAAACCTCAATGCCCACAAAAATCATCCAGGGTTCTTACTAAAAAGACAGGTCCTGGGATCAGCTCCAAAATAGTATTTCTGTGGTGGGGCCCAGAAATCTATGTTTTAATTTAAAAAGCATCACAGATGACTCCTGAGACAGGTGGTCCACAAAGCCCATTTGAGAACCCACAGATAATACAGAAAAAGAAACAGATCAATTAGGTACTATGATTCCAAATCAAAACTGTTTTTGCTCTTTATGTATTAGCATCTACAACACTGGAAATATATCAAACTGATAAGATCATCAAGGTCTGCTTATAAAATCATGAATCCCAGTCTATTATTTGGTCAACAAAAGAAACAGGGATAAATTTGTCCAATATTGCATTTTGGCACTATATTTTTAAATAAACTGCATTTCAATATAATTTATGTTCTTAAAAGTCACTGCTTTGTGACAAATTGGAAACCTTCCATCAGTACCATTAAGACCAACAATTTAGAGTATGCAAATTAGTTTTATTACTATTTGCTTATTTGCATCCTCCCCTATTCCAAAAGGAATTTGAGAGGGTGTGTAAATTCATTTCAGTGAACATTTTCACCTCGCACAGAAAATTTGTTTTTTATAATAAGTGAAAAGGCTGACAGCTATCATTAAAAGGTGGCATCACGAGGAAAGATAATGTTCTTTTTATGAAGTCCTTTTACAATTTCTCAAAGTCCTAATATTTTCTGTAGTTTCATGGCTATACATAGTAGGATTGTTAAAGAAAAAAGTGAGAATAAGGACCTTTCCATAGCTAAAATTTTATCACAATATCTACCATTGCAAAATCTTTCAAAACACCCACATTATGAAATTATATAAAAATATTAAGTTACAATATTGAGTCCTTCACTAGAATCAGAATGAGATGATCAAAAAAGCTTTTAAATAAAAAGGTATATATTTTAAAACAGTGTAACAGCATGTCTTTAAATTATTATTTAGCATGTTTGGTGAGACACAAGAAATCCATATACTTGTGCAATTAGAAAAAGGTCTAAGTGCTATTAAAAATCTATTCATGCAGTGTGATAAAACTGATGCCCTTACTGCATACTGATTTCTGGAAAGAAAAGAGGTTATTTCTAACGTTCCAAAGGTTACACTGCATTAAGACCTTACTCCCAATCTATTATTTTAAATTGGGCTAAAGAATAGTAATTGAGTGGTACATTAAATTTTCCAGTATAGAGGAATTCAAGTTGCCTGCCATAATGAAAGGTAGTTCTAAATAAGAATATATGTGCAACTTCAAATTTCAGTTATGCTAGATTTATTTTTCTTAAATATTTTATTATATATTGCTAGTATAAAAATCAGAATTCTATGACATACCATAATCTATTATCCCATTTTAAGTAATTTTCTTCTGGTAACAATCTTTTGCAATTAAAAAGACGATCCCAAAAACAAGTAATGTTTAAAGAGATTGTTTATATTCATGAATATACTAAAATTAAAATTAAAATATTGGAATACTGTAAACACTCACGATACATATATTTAAAATACAACTCTTTGAAAAAATTAAAAATCAATAAATCACAATGCTCACAATAAAAATCTCAAGATGGTGGTGAGAATAAGATTTGTAGTTTTCTAGAACTGAGCTAATAAAATCCCCAAGAATTTTTAAAACTTAGAAAACTTCACCACAAGAAATAATATCAATATAAATATACCAAACTTTTGGTGATGGCATTGTATTACAAAGCTTAGGAAACTGACAAAGACAACATTTTTGAGCAGGTGGATGGGATCAGAATACTAAGATTTTTGGATTCCAGCTTTCCCTTTCTCTTCCCATTAAGCAACAGGACTCTCATTTATACACCATTGACACTATGAATTCACAGCCACTACTTTCAAAGATTTGAAGCACCTGAAAAAAAGGCAAGTAAGAAAATTAGTCACTTTTTAGAGGCCAGGCACAGTGGCTCATGCCTAAAATCCCAGCACTTTGGGAGGCTGAGGCGGGTGGATCACTTGAGGACAGGAGTTTGAGACCAGCCTGGCCAACATGGTGATACCCTGTCTCTACTAAATATACAAAATTAGCCTGGCACACTCCTGTAATTCCAGCTACTTGGGAGGCTAAGGTAAAAGAATCACTTGAACTCAGGAGGCAGAGGTTGCAGTGAGCTAAGATTGTGCCACTGCACTCCAGCCTGGGTGACAGAGCGAGACTCTGTCTCAAAAAAAAAAGAAAAGTAAATTAGTCACTTTTTGTTCCCCATGGTCTTTTTAACCACAAAATAAATAGGAACACTGAAATAAAACCAAACTAATAATACACACACAGACACAGACACAGGTACAGACACACACACAGAGTCATACATATGATATAATACTTTCATTATGAAGCTCTGCTTTTCAATATTCTCAAAGACAAATTGGATTGTAAATGACTTTGCCTGATTCTTTATTCTAAATGCCCTGAGAAAGTGATTAAATGCACTTTTCAAACCTTGTACTAGAAGGCAGTTTCCACGGCCACCACAACCCATTAATTTGCCAGCAAAAACAAATAATGATTCCTAGCTCACCACAGCAGCTATAGAAAGACATCTAGAAAGATTTTGCAGATCACTCTGTAAGCAGTTCAATTTAAAAGCTATTGTGTTTCAACACCAGCCCACTGCACAGTGCAACAGTCCAAAGTAAACCCTACAAAAACATCAATTTCATTTATTTAAATTTGTCAAAGGCAAAATCAGTAGACATCTAAGCAAACTGCATACCAACAGCAAATCAGATCTAATACTCTGTATCTGGACTCAATATGCATTAAAGCCTAAGCCTGAATTACAATGGGGTGCCAGAGAAAGGGTGGGTAACTTGTGAAATGGCAGGCATCCTGTGAGGCATCTGGGCAACAAGGATACAAAGTGCTATTTCAATATTACTCAGTTTTTACAGAATAACATCTTTCAGTTGTTAAGATATGAAATCCCATCTGTCCCATTAAACATTATGTGAAATCCTGTCAGAGCAATCCACAGGTAGTATGGGTTGTTTTGTTGTTGTTGTTGTTTTTTAAAGACAGGGTCTTACTCTGTCATCCAGGCTGGAGTGCGGTGGTGCAATCATTGCTCACTACAACCTCAAACTCCTGGGCTCAAGCAATCCTCCCGCCTCAGCCTCCCAAAGTTCTGGGATTACAGGCATGAGCCACCATGCCAGCTGATAGTATGCATTTTATTCTAGAAGAACTCCAAAACCAGTATTTATCATAAATGAAGGATACGCCAAAGGACAGAATACTCACAATCAGAACATGTAAGTTGACTGTATTACAGACATAAATCTATTTGATTTGACCGAATTCAAAATGTAAAATACATTTAAACTTTAGTTTTTATATTTTCAATTATTACTAAATAACCAATTAAAACAAAGCCCTCAATATGATAAAATCTATGTTCTCTTTTTAAAACAAATTACATAGCTAATATCTATTGAGCTCTTACCATGTGCCATGCACTGTTTTTGAGAGCTTTACGTATTTTCTCAGTCATTCATCGCCAAAGCCCTATGAAGTATGCTCTACTATGATCTGCACTAGACATATGAGGAAACTAGGTAACAAATGAGTTAAGAAACTTGCCCACATCTCACAGCTGGTTAGTGGTGGAACTAGGATCAGAACTCCAAATCTGAATCCAAAATTCATACTGGATCACTGGGTAGCGACAAAATGAGTGTGGTAAACTAGGAAGAATACTGGTCAGCAAGCTGTTGAGACCGGTTCTGATCCCACACTGATGGTGTTACATCAAGGAGGCAATTAACTTCACCTCACTGGGGTCATATTTACTTATTAATCAGATGAAGGATTATTCCTTCATCCTCTGTTTGTCTGCCACATTGTGCAATGGCTCCCTTAGTGCCTCCTGCCATTTCCCCAAGAGCCAGATTTTCAGGGCAGACCCAGGCCATCCTCTTGCCTGTTCCCACACCCGTGTATAGTGGGACATTTTCCCACTTCTTTCACCTCTTCTTTTAAGGATAGGTAAGGTGGCCAGGTGGGAAGAGGTCTTGCTATCACTTCTGTTCTCTCTCCTTCCAGAAGAAAGATGGACCCAGGATTCTGCCCTAATAAAGTGGCTCAGGCACTGAAGGAAAACATGCTCAATATTGACCCATTGTCCTTAGATATTGGACAGACTGGCTTTTCCTAAAATTGCAGTGTTTTAGAATGACACTCCTGGGTTTGATGGTGAAATAGGTAGAGATTCAGGAGGACAGAAGTCTCATTTAAGGCTCTTATTTTAAGGCTCACATTTTAAAATCACTTGCCTACGTTTAGGAGTTATCAGGTACTTGGTCGGATTAATAAAACACTGCTTTTATTTCCACATGGCCATTGTTCTTGTATAAACAGCTCTCCTGACTGGAACAGAGAGATTCTGGGGATTCAATCATTCTTCTTTCCTGACTTTGAAGTTATGTCTGCTACATCCCTCATCACCTTCTCCTGGGGTAACTTGTGGTTGACCATTTTGAGGGTTCTGCACAACAAATTGTTTTGATTCTTCCTTGCTTGTCCCACCTTCAAGCACTTCAGTTTCCTCAGATACGTTAGATGAGCAGTAACAACTAATTATCAGCTTTTCATTCTCCTTAAGTTCAAATGTGTGCTGTAGAATTCCATACAGCTTTCTTGTATTTTAATTTCTTTTATTATCATATTCCAGATTTGTCTACTTTTGTTACCTCTCTCTGCTTCATAATAATTAGAAGGGAATTTTGTTTTATTTTCTTTCCAAAAGACCAGATTTAACATGTACTTTTCAACTCATATATATTTTTTGTATTCTATTTTACAAAATCAGCATTGATCCCTCTTCTGTTTTGATTCGTTTTTCTTTTATTTTATATCCCTATACTTTAAAAATGGTGATCTTTATAACTTTAGCCATGTCCTACATGTTTTGAAATAAAGCATTTTATTTCCTGGGTTTTAGAAAAAAGTTTGCATTTCTTCTTTAAATGCATTCTTTAATCTGAAAGTACATTTCTTACTTTACAACTGGTCTGGTACCCTTTTAAATTATTTAAGTCTCATTTCATTGCTTAAGGTCAAAGAATGCAAAATCTTTAAGCTTCCTTTATGCCTAAATACATTCTTGATTTTTTGAAAATATTCACTGGATATACTCCTAAAAGTGGGTATTATCTGTTCAAGAGATATAAGGTTTTAGCTATATTTACTAAATAAGTTTTTGATTACTTAATTTTCTTACTTATATCTGTCTACTAGAAATATCTAATATGAGAGAAATACATTACAGTCACACATTGTAACTATTTTATCAATTTCTCCTCACATTTTGAATAGATTTTTCCTTTACATATTTATTTGGTTGCCATATTTTTTGTGCAAATAGGTTTGTGCTTATTACTTTCTTTACAAATTACCCTTTTTTCATTTTATAATGTTCCTTTTTATCTTGTTAAATGCTTTTAATTAACTGTAAATCTCACTTTCTTGTTCATATTTGCTTAATATCTCTTTCCTTACCTTCTTATTTTCAACTTTTATCACTTGATTAAGGTGCTTTAACTATAAATGGCCTGTAGCTAGTTTTTGTTTTTATTCCAATTTGTAAGTCTGTCTTTTGATGAGAAAATTCAGTCCATTCATATTCAAGATGAGAAATATTTGATTTTATTTCTTCCATCTTTATTACTTTTAAATACTTATTATTTATTTTACATTTGTTTTCTTTCTTTCTTATTTTTTTTCTGGCTTTGTAAAACTGCTATTTGTTCCTTTATTTTCCTTTGTGAATACTGAATTCTCACCATATTTTTGTATCTATTAATGGTTATCTTCTGAGAAAAACAAAAGCTGAAAAAAATAAGCTTTGCTATATAGAGCTGTAAGACTGTACTTATTTGGCTTATAGTCCAGCAACTGTTGAGAAAGTTGATGCATCAGCCAGGTGCCATGGCTCACGCCTGTAATCCCAGCACTTCGGGAGGCTGGGGTGAGATCACCTGAGGTCAGGAGTTTGAGACCAGCGTGGTCAACATGGGGAAACCCCATCTCTACTAAAAACACAAAAATTATCCAGGCACGGTGGCGCATGCCTGTAATCCCAACTACTCAGAGGCTGAGGCAGGAGAATCACTTGAACCTGGGAGGTGGAGGTTGCAGTGAGATGAGATTGCGCCACTGCACTCCAGCCAGGGTGACAGAGCAAGACTCCATTAAAAAAAAAAAGGGAAAGAGAGAGAATGAGCGAGAAAAAGAAAGTTTACACATCAAAAGTATCTTCTGTATCCCTGGACATGAATATACTCAAATAGAAGAAAGTTTTCTTCCAAGAAAGCCTAGGGTTTGCCAGATACAGGCCTCATACACTGTTACAGGTTTTATGTATAGCAGCTGCACTCTCCTGAAGCCCTAGTACTTATAATTGCCTCTTCCTTTCTAAACAGGACCAGAACGAGTTTACTAGCACAAGTTTTAACTAAATTTTGCACAAGAAGTCTGGGGAGATACAGAACTCCTAGTTCCTTCTCATAATCAGATACATACTTCTCTACCATTACCTGTAAACAAGGTATTAA", "alternate_allele_vcf": "T"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "adaptor related protein complex 3 subunit beta 1"}}], "symbols": [{"value": {"type": "Preferred", "value": "AP3B1"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "5", "accession": "NC_000005.10", "start": 78000522, "stop": 78294698, "display_start": 78000522, "display_stop": 78294698, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "5", "accession": "NC_000005.9", "start": 77298149, "stop": 77590527, "display_start": 77298149, "display_stop": 77590527, "strand": "-", "variant_length": 292379, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "8546"}, {"db": "OMIM", "id": "603401", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:566"}]}], "xrefs": [{"db": "OMIM", "id": "603401.0005", "type": "Allelic variant"}], "comments": [{"text": "Deletion of exon 15 plus intronic flanking sequences from AP3B1 (NG_007268.1)", "type": "public", "datasource": "NCBI curation"}], "id": 21414}], "names": [{"value": {"type": "Preferred", "value": "NM_003664.5(AP3B1):c.1474-7072_1650+921del"}}], "xrefs": [{"db": "ClinGen", "id": "CA340565"}], "id": 6375}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Hermansky-Pudlak syndrome 2"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0011997"}]}, {"value": {"type": "Alternate", "value": "Platelet defects and oculocutaneous albinism"}}], "symbols": [{"value": {"type": "Preferred", "value": "HPS2"}, "xrefs": [{"db": "OMIM", "id": "608233", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1287"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "9435"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301464"}, {"source": "BookShelf", "value": "NBK1287"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0011997"}, {"db": "MedGen", "id": "C1842362"}, {"db": "Orphanet", "id": "79430"}, {"db": "OMIM", "id": "608233", "type": "MIM"}]}], "id": 1768}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 64250}, "record_status": "current", "title": "NM_003664.5(AP3B1):c.1474-7072_1650+921del AND Hermansky-Pudlak syndrome 2", "clinvar_assertions": [{"id": 26939, "submission_id": {"local_key": "603401.0005_HERMANSKY-PUDLAK SYNDROME 2", "submitter": "OMIM", "title": "AP3B1, EX15DEL_HERMANSKY-PUDLAK SYNDROME 2", "submitter_date": "2019-09-30"}, "clinvar_accession": {"acc": "SCV000026939", "version": 3, "type": "SCV", "date_updated": "2019-10-02", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2006-07-01"}], "external_ids": [{"db": "OMIM", "id": "603401.0005", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Kotzot et al. (1994) described an inbred Turkish family in which a boy and a girl related as first cousins, and in each case the offspring of consanguineous parents, had tyrosinase-positive oculocutaneous albinism, recurrent bacterial infections, granulocytopenia, intermittent thrombocytopenia, microcephaly, protruding midface, rough and projecting hair, and mild mental retardation (HPS2; 608233). Using genetic linkage analysis and targeted gene sequencing, Jung et al. (2006) defined a homozygous genomic deletion in AP3B1. The mutation led to in-frame skipping of exon 15 and thus perturbed proper assembly of the heterotetrameric AP3 complex. Despite distinct ultramorphologic changes suggestive of aberrant vesicular maturation, no functional aberrations were detected in neutrophil granulocytes. However, a comprehensive immunologic assessment revealed that natural killer (NK) and NKT-cell numbers were reduced in the AP3-deficient patients. The findings extended the clinical and molecular phenotype of human AP3 deficiency and provided insight into the role of the AP3 complex for the innate immune system. The deleted interval spanned 8,168 bp, including a large part of intron 14, the complete exon 15, and a small part of intron 15. Loss of exon 15 resulted in the absence of amino acid 49 to 550 while preserving the reading frame."}, "citations": [{"ids": [{"source": "PubMed", "value": "8042664"}]}, {"ids": [{"source": "PubMed", "value": "16537806"}]}], "xrefs": [{"db": "OMIM", "id": "608233", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "AP3B1, EX15DEL"}}], "attributes": [{"type": "NonHGVS", "value": "EX15DEL"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "AP3B1"}}]}], "xrefs": [{"db": "OMIM", "id": "603401.0005", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "HERMANSKY-PUDLAK SYNDROME 2"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000007011", "version": 3, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2004-01-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only", "literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In all 10 affected members from 2 families with congenital generalized lipodystrophy-1 (CGL1; 608594) from southeastern Brazil, Gomes et al. (2004) identified homozygosity for a 1.036-bp deletion encompassing nucleotide 50 of exon 3 to nucleotide 534 within intron 4 of the AGPAT2 gene, resulting in the skipping of exons 3 and 4 and inducing the deletion of nucleotides 317-588. The mutation causes a frameshift and premature termination codon, Gly106fsTer188. Gomes et al. (2004) noted that this mutation had previously been described in a large consanguineous pedigree from Portugal by Agarwal et al. (2002)."}, "citations": [{"ids": [{"source": "PubMed", "value": "11967537"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": "14715872"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000006632", "version": 1, "measures": [{"type": "deletion", "names": [{"value": {"type": "Preferred", "value": "NM_006412.4(AGPAT2):c.366_588+534del"}}], "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001012727.2:c.366_492+910del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_006412.4:c.366_588+534del"}, {"type": "HGVS, genomic, top level", "value": "NC_000009.12:g.136676051_136677087del", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000009.11:g.139570503_139571539del", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_006412.3:c.366_588+534del"}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_006412.4:c.366_588+534del"}]}, {"type": "MolecularConsequence", "value": "splice donor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001575"}, {"db": "RefSeq", "id": "NM_001012727.2:c.366_492+910del"}]}, {"type": "MolecularConsequence", "value": "splice donor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001575"}, {"db": "RefSeq", "id": "NM_006412.4:c.366_588+534del"}]}], "cytogenic_locations": ["9q34.3"], "sequence_locations": [{"assembly": "GRCh38", "chr": "9", "accession": "NC_000009.12", "start": 136676051, "stop": 136677087, "display_start": 136676051, "display_stop": 136677087, "variant_length": 1037, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 136676050, "reference_allele_vcf": "ACCCTGGCCTCTCCCAGACACCCTAGGATGCACTGCACCCCTGGAGGCTGGGGACCAGGAAGTCCAGAGTCTGGAGGCGCTGCTTACAATGAGCTCCACCCACCCTGAGCTCTGGTCTGGCCTGATACTACACCAAAAGCCTGGCTTGTCCAGACCCACTGCCCATGCCCTGAAGCCCACCCCAGCCAGGCACAGGCCCAGAAATGAGCCTCCTGAGAGCTCTGCAGCAGAGGCGAGCGGCCCGGCTCCCCACCCCTCTACCTGCCCAGCCTCGCAGGCCAAGCACTGGGTGCCCACCAAGGGCAGCTGGTCACTCTGGGCTCTGTGTGGGCAAAAGGCCCAAGGGGCTGCCCTCCCTGGTCGGTCAGGGGGCAAGTGCAGGAAGGGGCAAGGAGGCCCTGTCCCCAACTCAGTGGGAGGAGTCCCTTGTGTGTCAAGGGTCCTCAGCTCGGCTGGTGGTCACCTGCTGCCTTAAGCCAGCCTGACCCCGCCTCCCCAGCCTGCACCCACCCAGGGAGGGCTGGGCTCAGCCTACCTGTGCCTGGACTGCCAGGTAGAAGGCGCCCTTCTTAAAAGGCAGCAGGTCCCCATTGTCGTTGCGAGTACCCTCGGGATAGATCCACACTTTGAGCTGCAGGGAGAGGAGAGCCTGGACTGACCTCACGCCCAGGCCACCCCAGAAAGGCCACGCCGCCTCGCCTCCTAAGAAGCCCCACTTCGCAAAGCAGCTGGCATGGGACCCCATCTGCGGAGCATGGATGATGTAGGGGTCTGGCGTGGGACCCCACCTGCGGAGCATGGATGATGTGGGGGTCTTGTTTTTTCTGCCAAAACCAAGTCACAAGCTGGCCCCTGCCTGGCCCCGCCCAGGCCCCACCCCAACCCCACCGAGCCCGGCCCTGCACACTCACGTTCTCCCTGACCATGCGCTCGCCCAGGTCGGCCATCACTGTCATGGCAGTGCTAGAGCGCTGCCGGTTGATGAAGAAGACGCCCCCGAGGTACATGATGAGGCCCACGGGCCCCAGGAAGAGCAGC", "alternate_allele_vcf": "A"}, {"assembly": "GRCh37", "chr": "9", "accession": "NC_000009.11", "start": 139570503, "stop": 139571539, "display_start": 139570503, "display_stop": 139571539, "variant_length": 1037, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 139570502, "reference_allele_vcf": "ACCCTGGCCTCTCCCAGACACCCTAGGATGCACTGCACCCCTGGAGGCTGGGGACCAGGAAGTCCAGAGTCTGGAGGCGCTGCTTACAATGAGCTCCACCCACCCTGAGCTCTGGTCTGGCCTGATACTACACCAAAAGCCTGGCTTGTCCAGACCCACTGCCCATGCCCTGAAGCCCACCCCAGCCAGGCACAGGCCCAGAAATGAGCCTCCTGAGAGCTCTGCAGCAGAGGCGAGCGGCCCGGCTCCCCACCCCTCTACCTGCCCAGCCTCGCAGGCCAAGCACTGGGTGCCCACCAAGGGCAGCTGGTCACTCTGGGCTCTGTGTGGGCAAAAGGCCCAAGGGGCTGCCCTCCCTGGTCGGTCAGGGGGCAAGTGCAGGAAGGGGCAAGGAGGCCCTGTCCCCAACTCAGTGGGAGGAGTCCCTTGTGTGTCAAGGGTCCTCAGCTCGGCTGGTGGTCACCTGCTGCCTTAAGCCAGCCTGACCCCGCCTCCCCAGCCTGCACCCACCCAGGGAGGGCTGGGCTCAGCCTACCTGTGCCTGGACTGCCAGGTAGAAGGCGCCCTTCTTAAAAGGCAGCAGGTCCCCATTGTCGTTGCGAGTACCCTCGGGATAGATCCACACTTTGAGCTGCAGGGAGAGGAGAGCCTGGACTGACCTCACGCCCAGGCCACCCCAGAAAGGCCACGCCGCCTCGCCTCCTAAGAAGCCCCACTTCGCAAAGCAGCTGGCATGGGACCCCATCTGCGGAGCATGGATGATGTAGGGGTCTGGCGTGGGACCCCACCTGCGGAGCATGGATGATGTGGGGGTCTTGTTTTTTCTGCCAAAACCAAGTCACAAGCTGGCCCCTGCCTGGCCCCGCCCAGGCCCCACCCCAACCCCACCGAGCCCGGCCCTGCACACTCACGTTCTCCCTGACCATGCGCTCGCCCAGGTCGGCCATCACTGTCATGGCAGTGCTAGAGCGCTGCCGGTTGATGAAGAAGACGCCCCCGAGGTACATGATGAGGCCCACGGGCCCCAGGAAGAGCAGC", "alternate_allele_vcf": "A"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "1-acylglycerol-3-phosphate O-acyltransferase 2"}}], "symbols": [{"value": {"type": "Preferred", "value": "AGPAT2"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "9", "accession": "NC_000009.12", "start": 136673143, "stop": 136687457, "display_start": 136673143, "display_stop": 136687457, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "9", "accession": "NC_000009.11", "start": 139567594, "stop": 139581910, "display_start": 139567594, "display_stop": 139581910, "strand": "-", "variant_length": 14317, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "10555"}, {"db": "OMIM", "id": "603100", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:325"}]}], "xrefs": [{"db": "dbVar", "id": "nssv3761633"}, {"db": "dbVar", "id": "nsv1067865"}, {"db": "OMIM", "id": "603100.0009", "type": "Allelic variant"}], "comments": [{"text": "Deletion in AGPAT2 (NG_008090.1) beginning in exon 3 and ending in intron 4", "type": "public", "datasource": "NCBI curation"}], "id": 21671}], "names": [{"value": {"type": "Preferred", "value": "NM_006412.4(AGPAT2):c.366_588+534del"}}], "xrefs": [{"db": "ClinGen", "id": "CA277954"}], "id": 6632}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Congenital generalized lipodystrophy type 1"}, "xrefs": [{"db": "Genetic Alliance", "id": "Congenital+Generalized+Lipodystrophy+Type+1/1829"}, {"db": "MONDO", "id": "MONDO:0012071"}]}, {"value": {"type": "Alternate", "value": "BRUNZELL SYNDROME, AGPAT2-RELATED"}, "xrefs": [{"db": "OMIM", "id": "608594", "type": "MIM"}]}], "symbols": [{"value": {"type": "Preferred", "value": "CGL1"}, "xrefs": [{"db": "OMIM", "id": "608594", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "BSCL1"}, "xrefs": [{"db": "OMIM", "id": "608594", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1212"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "84"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301391"}, {"source": "BookShelf", "value": "NBK1212"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0012071"}, {"db": "MedGen", "id": "C1720862"}, {"db": "Orphanet", "id": "528"}, {"db": "OMIM", "id": "608594", "type": "MIM"}]}], "id": 1835}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 64514}, "record_status": "current", "title": "NM_006412.4(AGPAT2):c.366_588+534del AND Congenital generalized lipodystrophy type 1", "clinvar_assertions": [{"id": 27207, "submission_id": {"local_key": "603100.0009_LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 1", "submitter": "OMIM", "title": "AGPAT2, 1,036-BP DEL_LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 1", "submitter_date": "2014-11-26"}, "clinvar_accession": {"acc": "SCV000027207", "version": 2, "type": "SCV", "date_updated": "2014-11-29", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2004-01-01"}], "external_ids": [{"db": "OMIM", "id": "603100.0009", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In all 10 affected members from 2 families with congenital generalized lipodystrophy-1 (CGL1; 608594) from southeastern Brazil, Gomes et al. (2004) identified homozygosity for a 1.036-bp deletion encompassing nucleotide 50 of exon 3 to nucleotide 534 within intron 4 of the AGPAT2 gene, resulting in the skipping of exons 3 and 4 and inducing the deletion of nucleotides 317-588. The mutation causes a frameshift and premature termination codon, Gly106fsTer188. Gomes et al. (2004) noted that this mutation had previously been described in a large consanguineous pedigree from Portugal by Agarwal et al. (2002)."}, "citations": [{"ids": [{"source": "PubMed", "value": "14715872"}]}, {"ids": [{"source": "PubMed", "value": "11967537"}]}], "xrefs": [{"db": "OMIM", "id": "608594", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "AGPAT2, 1,036-BP DEL"}}], "attributes": [{"type": "NonHGVS", "value": "1,036-BP DEL"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "AGPAT2"}}]}], "xrefs": [{"db": "OMIM", "id": "603100.0009", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 1"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000006409", "version": 4, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2006-07-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Oates et al. (2006) examined methylation at the promoter region of the AXIN1 gene in monozygotic twins discordant for a caudal duplication anomaly (607864). Methylation of the promoter region in the peripheral blood mononucleated cells was variable among individuals. 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"assembly_status": "current"}, {"assembly": "GRCh37", "chr": "22", "accession": "NC_000022.10", "start": 40742503, "stop": 40762576, "display_start": 40742503, "display_stop": 40762576, "strand": "+", "variant_length": 20074, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "158"}, {"db": "OMIM", "id": "608222", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:291"}]}], "id": 471313}], "names": [{"value": {"type": "Preferred", "value": "NC_000022.10:g.(?_40742514)_(40762546_?)dup"}}], "id": 459612}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Adenylosuccinate lyase deficiency"}, "xrefs": [{"db": "Genetic Alliance", "id": "Adenylosuccinase+Deficiency/230"}, {"db": "MONDO", "id": "MONDO:0007068"}, {"db": "SNOMED CT", "id": "15285008"}]}], "symbols": [{"value": {"type": "Preferred", "value": "ADSLD"}, "xrefs": [{"db": "OMIM", "id": "103050", "type": "MIM"}]}], "attributes": [{"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "550"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "23519317"}], "type": "practice guideline", "abbrev": "ACMG, 2013"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0007068"}, {"db": "MedGen", "id": "C0268126"}, {"db": "Orphanet", "id": "46"}, {"db": "OMIM", "id": "103050", "type": "MIM"}]}], "id": 619}, "date_created": "2017-12-26", "date_last_updated": "2022-04-23", "id": 1271018}, "record_status": "current", "replaces": ["RCV001294714"], "title": "NC_000022.10:g.(?_40742514)_(40762546_?)dup AND Adenylosuccinate lyase deficiency", "clinvar_assertions": [{"id": 1223576, "submission_id": {"local_key": "1584054|MedGen:C0268126", "submitter": "Invitae", "submitted_assembly": "GRCh37", "submitter_date": "2017-10-05"}, "clinvar_accession": {"acc": "SCV000631358", "version": 1, "type": "SCV", "date_updated": "2017-12-26", "date_created": "2017-12-26", "org_id": "500031", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "replaced_list": [{"accession": "SCV001483602", "version": 1, "date_changed": "2021-04-22"}], "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["uncertain significance"], "comments": [{"text": "A gross duplication of the genomic region encompassing the full coding sequence of the ADSL gene has been identified. The boundaries of this event are unknown as the duplication extends beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this duplication is unknown, it may be in tandem or it may be located elsewhere in the genome. Duplication of the entire ADSL sequence has not been reported in the literature in an individual affected with an ADSL-related disease. In summary, the exact genomic location of this variant is unknown and the impact of this duplication on ADSL protein function has not been established. Therefore, it has been classified as a Variant of Uncertain Significance."}], "date_last_evaluated": "2017-03-22"}], "external_ids": [{"db": "Invitae", "id": "1584054"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "Invitae Variant Classification Sherloc (09022015)"}, "citations": [{"ids": [{"source": "PubMed", "value": "28492532"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NC_000022.10:g.(?_40742514)_(40762546_?)dup"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "ADSL"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "MedGen", "id": "C0268126", "type": "CUI"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000539041", "version": 3, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2017-12-26"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "pathogenic", "date_last_evaluated": "2019-11-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000458651", "version": 2, "measures": [{"type": "duplication", "names": [{"value": {"type": "Preferred", "value": "NC_000023.10:g.(?_69080668)_(69177002_?)dup"}}], "attributes": [{"type": "HGVS, genomic, top level, previous", "value": "NC_000023.10:g.(?_69080668)_(69177002_?)dup", "integer_value": 37}], 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"300451.0011", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0012", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0013", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0016", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0017", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0019", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0023", "type": "Allelic variant"}]}, {"value": {"type": "Alternate", "value": "CST syndrome"}}, {"value": {"type": "Alternate", "value": "Ectodermal dysplasia 1, anhidrotic"}}, {"value": {"type": "Alternate", "value": "Christ-Siemans-Touraine syndrome"}}], "symbols": [{"value": {"type": "Preferred", "value": "XHED"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "EDA1"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "ED1"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "EDA"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "XLHED"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "HED1"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "ECTD1"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow-growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, and at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1112"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "10427"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301291"}, {"source": "BookShelf", "value": "NBK1112"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0010585"}, {"db": "MedGen", "id": "C0162359"}, {"db": "Orphanet", "id": "181"}, {"db": "Orphanet", "id": "238468"}, {"db": "OMIM", "id": "305100", "type": "MIM"}]}], "id": 6534}, "date_created": "2017-12-26", "date_last_updated": "2022-04-23", "id": 1273787}, "record_status": "current", "title": "NC_000023.10:g.(?_69080668)_(69177002_?)dup AND Hypohidrotic X-linked ectodermal dysplasia", "clinvar_assertions": [{"id": 1222234, "submission_id": {"local_key": "2457053|MedGen:C0162359", "submitter": "Invitae", "submitted_assembly": "GRCh37", "submitter_date": "2020-02-06"}, "clinvar_accession": {"acc": "SCV000630016", "version": 3, "type": "SCV", "date_updated": "2020-04-09", "date_created": "2017-12-26", "org_id": "500031", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["pathogenic"], "citations": [{"ids": [{"source": "PubMed", "value": "24689965"}]}, {"ids": [{"source": "PubMed", "value": "27305980"}]}], "comments": [{"text": "This variant is a gross duplication of the genomic region encompassing exon 2 of the EDA gene. While the exact position of the duplicated exon cannot be determined from this data, the duplicated copy of this region is likely in tandem and may result in an absent or disrupted protein product. Duplication of exon 2 has been reported in individuals affected with X-linked hypohidrotic ectodermal dysplasia (PMID: 27305980, 24689965). Sub-genic duplications are generally in tandem (PMID: 25640679), and result in an absent or disrupted protein. Loss-of-function variants in EDA are known to be pathogenic (PMID: 9683615). For these reasons, this variant has been classified as Pathogenic."}], "date_last_evaluated": "2019-11-01"}], "external_ids": [{"db": "Invitae", "id": "2457053"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "Invitae Variant Classification Sherloc (09022015)"}, "citations": [{"ids": [{"source": "PubMed", "value": "28492532"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NC_000023.10:g.(?_69080668)_(69177002_?)dup"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "EDA"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "Hypohidrotic X-linked ectodermal dysplasia"}}], "xrefs": [{"db": "MedGen", "id": "C0162359", "type": "CUI"}]}]}, "citations": [{"ids": [{"source": "PubMed", "value": "28492532"}], "type": "general"}]}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000554988", "version": 1, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2017-12-26"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "uncertain significance", "date_last_evaluated": "2017-08-07"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000471419", "version": 1, "measures": [{"type": "duplication", "names": [{"value": {"type": "Preferred", "value": "NC_000017.10:g.(?_56769999)_(56774226_?)dup"}}], "attributes": [{"type": "HGVS, genomic, top level, previous", "value": "NC_000017.10:g.(?_56769999)_(56774226_?)dup", "integer_value": 37}], "cytogenic_locations": ["17q22"], "sequence_locations": [{"assembly": "GRCh38", "chr": "17", "accession": "NC_000017.11", "inner_start": 58692638, "inner_stop": 58696865, "display_start": 58692638, "display_stop": 58696865, "variant_length": 4228, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "17", "accession": "NC_000017.10", "inner_start": 56769999, "inner_stop": 56774226, "display_start": 56769999, "display_stop": 56774226, "variant_length": 4228, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "RAD51 paralog C"}}], "symbols": [{"value": {"type": "Preferred", "value": "RAD51C"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "17", "accession": "NC_000017.11", "start": 58692573, "stop": 58735611, "display_start": 58692573, "display_stop": 58735611, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "17", "accession": "NC_000017.10", "start": 56769962, "stop": 56811691, "display_start": 56769962, "display_stop": 56811691, "strand": "+", "variant_length": 41730, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "5889"}, {"db": "OMIM", "id": "602774", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:9820"}]}], "id": 467050}], "names": [{"value": {"type": "Preferred", "value": "NC_000017.10:g.(?_56769999)_(56774226_?)dup"}}], "id": 471419}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Fanconi anemia complementation group O"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0013248"}]}], "symbols": [{"value": {"type": "Alternate", "value": "FANCO"}, "xrefs": [{"db": "OMIM", "id": "613390", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors \u2013 particularly of the head and neck, skin, and genitourinary tract \u2013 are more common in individuals with FA."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1401"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301575"}, {"source": "BookShelf", "value": "NBK1401"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "PubMed", "value": "20301753"}, {"source": "BookShelf", "value": "NBK5192"}], "type": "review", "abbrev": "GeneReviews"}, {"type": "practice guideline", "abbrev": "FARF, 2008", "url": "http://www.fanconi.org/images/uploads/other/Guidelines_for_Diagnosis_and_Management.pdf", "citation_text": "Fanconi Anemia Research Fund, Guidelines for Diagnosis and Management, 2008"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0013248"}, {"db": "MedGen", "id": "C3150653"}, {"db": "Orphanet", "id": "84"}, {"db": "OMIM", "id": "613390", "type": "MIM"}]}], "id": 1880}, "date_created": "2017-12-26", "date_last_updated": "2022-04-23", "id": 1289734}, "record_status": "current", "title": "NC_000017.10:g.(?_56769999)_(56774226_?)dup AND Fanconi anemia complementation group O", "clinvar_assertions": [{"id": 1242530, "submission_id": {"local_key": "2437450|MedGen:C3150653", "submitter": "Invitae", "submitted_assembly": "GRCh37", "submitter_date": "2017-10-05"}, "clinvar_accession": {"acc": "SCV000649991", "version": 1, "type": "SCV", "date_updated": "2017-12-26", "date_created": "2017-12-26", "org_id": "500031", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["uncertain significance"], "comments": [{"text": "This variant is a gross duplication of the genomic region encompassing exons 1-3 of the RAD51C gene. The 5' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. The 3' boundary is likely confined to intron 3 of the RAD51C gene. The exact location of this variant in the genome is unknown. Duplication of exons 1-3 has not been reported in the literature in individuals with RAD51C-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.", "type": "public"}], "date_last_evaluated": "2017-08-07"}], "external_ids": [{"db": "Invitae", "id": "2437450"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "Invitae Variant Classification Sherloc (09022015)"}, "citations": [{"ids": [{"source": "PubMed", "value": "28492532"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NC_000017.10:g.(?_56769999)_(56774226_?)dup"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "RAD51C"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "MedGen", "id": "C3150653", "type": "CUI"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000633513", "version": 1, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2018-05-28"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "pathogenic", "date_last_evaluated": "2018-01-04"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000528365", "version": 1, "measures": [{"type": "duplication", "names": [{"value": {"type": "Preferred", "value": "NC_000023.10:g.(?_68890034)_(69177002_?)dup"}}], "attributes": [{"type": "HGVS, genomic, top level, previous", "value": "NC_000023.10:g.(?_68890034)_(69177002_?)dup", "integer_value": 37}], "cytogenic_locations": ["Xq13.1"], "sequence_locations": [{"assembly": "GRCh37", "chr": "X", "accession": "NC_000023.10", "inner_start": 68890034, "inner_stop": 69177002, "display_start": 68890034, "display_stop": 69177002, "variant_length": 286969, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "ectodysplasin A"}}], "symbols": [{"value": {"type": "Preferred", "value": "EDA"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "X", "accession": "NC_000023.11", "start": 69616113, "stop": 70039472, "display_start": 69616113, "display_stop": 70039472, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "X", "accession": "NC_000023.10", "start": 68835910, "stop": 69259321, "display_start": 68835910, "display_stop": 69259321, "strand": "+", "variant_length": 423412, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "1896"}, {"db": "OMIM", "id": "300451", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:3157"}]}], "id": 534391}], "names": [{"value": {"type": "Preferred", "value": "NC_000023.10:g.(?_68890034)_(69177002_?)dup"}}], "id": 528365}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Hypohidrotic X-linked ectodermal dysplasia"}, "xrefs": [{"db": "Genetic Alliance", "id": "Hypohidrotic+ectodermal+dysplasia+X-linked/3658"}, {"db": "SNOMED CT", "id": "239007005"}]}, {"value": {"type": "Alternate", "value": "ECTODERMAL DYSPLASIA, HYPOHIDROTIC, 1"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Anhidrotic ectodermal dysplasia X-linked"}}, {"value": {"type": "Alternate", "value": "Christ Siemens Touraine syndrome"}}, {"value": {"type": "Alternate", "value": "Ectodermal dysplasia 1"}}, {"value": {"type": "Alternate", "value": "ECTODERMAL DYSPLASIA 1, HYPOHIDROTIC, X-LINKED"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "ECTODERMAL DYSPLASIA 1, HYPOHIDROTIC/HAIR/TOOTH TYPE, X-LINKED"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}, {"db": "OMIM", "id": "300451.0001", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0002", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0003", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0004", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0005", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0006", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0007", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0008", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0009", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0010", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0011", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0012", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0013", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0016", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0017", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0019", "type": "Allelic variant"}, {"db": "OMIM", "id": "300451.0023", "type": "Allelic variant"}]}, {"value": {"type": "Alternate", "value": "CST syndrome"}}, {"value": {"type": "Alternate", "value": "Ectodermal dysplasia 1, anhidrotic"}}, {"value": {"type": "Alternate", "value": "Christ-Siemans-Touraine syndrome"}}], "symbols": [{"value": {"type": "Preferred", "value": "XHED"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "EDA1"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "ED1"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "EDA"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "XLHED"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "HED1"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "ECTD1"}, "xrefs": [{"db": "OMIM", "id": "305100", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow-growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, and at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1112"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "10427"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301291"}, {"source": "BookShelf", "value": "NBK1112"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0010585"}, {"db": "MedGen", "id": "C0162359"}, {"db": "Orphanet", "id": "181"}, {"db": "Orphanet", "id": "238468"}, {"db": "OMIM", "id": "305100", "type": "MIM"}]}], "id": 6534}, "date_created": "2018-05-28", "date_last_updated": "2022-04-23", "id": 1494467}, "record_status": "current", "title": "NC_000023.10:g.(?_68890034)_(69177002_?)dup AND Hypohidrotic X-linked ectodermal dysplasia", "clinvar_assertions": [{"id": 1464200, "submission_id": {"local_key": "3424432|MedGen:C0162359", "submitter": "Invitae", "submitted_assembly": "GRCh37", "submitter_date": "2018-04-02"}, "clinvar_accession": {"acc": "SCV000754750", "version": 1, "type": "SCV", "date_updated": "2018-05-28", "date_created": "2018-05-28", "org_id": "500031", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["pathogenic"], "citations": [{"ids": [{"source": "PubMed", "value": "24689965"}]}, {"ids": [{"source": "PubMed", "value": "27305980"}]}], "comments": [{"text": "This variant is a gross duplication of the genomic region encompassing exon 2 of the EDA gene. While the exact position of the duplicated exon cannot be determined from this data, the duplicated copy of this region is likely in tandem and may result in an absent or disrupted protein product. Duplication of exon 2 has been reported in individuals affected with X-linked hypohidrotic ectodermal dysplasia (PMID: 27305980, 24689965). Sub-genic duplications are generally in tandem (PMID: 25640679), and result in an absent or disrupted protein. Loss-of-function variants in EDA are known to be pathogenic (PMID: 9683615). For these reasons, this variant has been classified as Pathogenic."}], "date_last_evaluated": "2018-01-04"}], "external_ids": [{"db": "Invitae", "id": "3424432"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "Invitae Variant Classification Sherloc (09022015)"}, "citations": [{"ids": [{"source": "PubMed", "value": "28492532"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NC_000023.10:g.(?_68890034)_(69177002_?)dup"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "EDA"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "MedGen", "id": "C0162359", "type": "CUI"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000638336", "version": 1, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2018-05-28"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "uncertain significance", "date_last_evaluated": "2017-10-12"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000531812", "version": 1, "measures": [{"type": "duplication", "names": [{"value": {"type": "Preferred", "value": "NC_000004.11:g.(?_77116840)_(77134716_?)dup"}}], "attributes": [{"type": "HGVS, genomic, top level, previous", "value": "NC_000004.11:g.(?_77116840)_(77134716_?)dup", "integer_value": 37}], "cytogenic_locations": ["4q21.1"], "sequence_locations": [{"assembly": "GRCh38", "chr": "4", "accession": "NC_000004.12", "inner_start": 76195687, "inner_stop": 76213563, "display_start": 76195687, "display_stop": 76213563, "variant_length": 17877, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "4", "accession": "NC_000004.11", "inner_start": 77116840, "inner_stop": 77134716, "display_start": 77116840, "display_stop": 77134716, "variant_length": 17877, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "scavenger receptor class B member 2"}}], "symbols": [{"value": {"type": "Preferred", "value": "SCARB2"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "4", "accession": "NC_000004.12", "start": 76158737, "stop": 76234532, "display_start": 76158737, "display_stop": 76234532, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "4", "accession": "NC_000004.11", "start": 77079889, "stop": 77135051, "display_start": 77079889, "display_stop": 77135051, "strand": "-", "variant_length": 55163, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "950"}, {"db": "OMIM", "id": "602257", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:1665"}]}], "id": 519942}], "names": [{"value": {"type": "Preferred", "value": "NC_000004.11:g.(?_77116840)_(77134716_?)dup"}}], "id": 531812}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Progressive myoclonic epilepsy"}, "xrefs": [{"db": "Genetic Alliance", "id": "Progressive+myoclonic+epilepsy/9622"}, {"db": "SNOMED CT", "id": "267581004"}]}, {"value": {"type": "Alternate", "value": "Myoclonic Epilepsies, Progressive"}}, {"value": {"type": "Alternate", "value": "Familial progressive myoclonic epilepsy"}}, {"value": {"type": "Alternate", "value": "Progressive myoclonus epilepsy"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0020074"}, {"db": "SNOMED CT", "id": "267581004"}]}, {"value": {"type": "Alternate", "value": "Myoclonus epilepsy"}}], "xrefs": [{"db": "MONDO", "id": "MONDO:0020074"}, {"db": "MedGen", "id": "C0751778"}, {"db": "Orphanet", "id": "308"}, {"db": "OMIM", "id": "PS254800", "type": "Phenotypic series"}]}], "id": 13597}, "date_created": "2018-05-28", "date_last_updated": "2022-04-23", "id": 1499290}, "record_status": "current", "title": "NC_000004.11:g.(?_77116840)_(77134716_?)dup AND Progressive myoclonic epilepsy", "clinvar_assertions": [{"id": 1469566, "submission_id": {"local_key": "2496472|MedGen:C0751778", "submitter": "Invitae", "submitted_assembly": "GRCh37", "submitter_date": "2018-04-02"}, "clinvar_accession": {"acc": "SCV000759831", "version": 1, "type": "SCV", "date_updated": "2018-05-28", "date_created": "2018-05-28", "org_id": "500031", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["uncertain significance"], "comments": [{"text": "This variant is a gross duplication of the genomic region encompassing exons 1-2 of the SCARB2 gene. The 5' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. The 3' boundary is likely confined to intron 2 of the SCARB2 gene. The exact location of this variant in the genome is unknown. Duplication of exons 1-2 has not been reported in the literature in individuals with a SCARB2-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of this duplication is currently unknown. In summary, the genomic location of this duplication is unknown and the impact of this variant on SCARB2 protein function has not been established. Therefore, it has been classified as a Variant of Uncertain Significance."}], "date_last_evaluated": "2017-10-12"}], "external_ids": [{"db": "Invitae", "id": "2496472"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "Invitae Variant Classification Sherloc (09022015)"}, "citations": [{"ids": [{"source": "PubMed", "value": "28492532"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NC_000004.11:g.(?_77116840)_(77134716_?)dup"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "SCARB2"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "MedGen", "id": "C0751778", "type": "CUI"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000638545", "version": 1, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2018-05-28"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "uncertain significance", "date_last_evaluated": "2017-09-13"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000531989", "version": 1, "measures": [{"type": "duplication", "names": [{"value": {"type": "Preferred", "value": "NC_000002.11:g.(?_233194517)_(233198703_?)dup"}}], "attributes": [{"type": "HGVS, genomic, top level, previous", "value": "NC_000002.11:g.(?_233194517)_(233198703_?)dup", "integer_value": 37}], "cytogenic_locations": ["2q37.1"], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "inner_start": 232329807, "inner_stop": 232333993, "display_start": 232329807, "display_stop": 232333993, "variant_length": 4187, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "inner_start": 233194517, "inner_stop": 233198703, "display_start": 233194517, "display_stop": 233198703, "variant_length": 4187, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "DIS3 like 3'-5' exoribonuclease 2"}}], "symbols": [{"value": {"type": "Preferred", "value": "DIS3L2"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 231961713, "stop": 232344350, "display_start": 231961713, "display_stop": 232344350, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 232826292, "stop": 233208677, "display_start": 232826292, "display_stop": 233208677, "strand": "+", "variant_length": 382386, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "129563"}, {"db": "OMIM", "id": "614184", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:28648"}]}], "id": 516316}], "names": [{"value": {"type": "Preferred", "value": "NC_000002.11:g.(?_233194517)_(233198703_?)dup"}}], "id": 531989}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Perlman syndrome"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0009965"}]}, {"value": {"type": "Alternate", "value": "Renal hamartomas nephroblastomatosis and fetal gigantism"}, "xrefs": [{"db": "Genetic Alliance", "id": "Renal+hamartomas+nephroblastomatosis+and+fetal+gigantism/6206"}]}, {"value": {"type": "Alternate", "value": "Nephroblastomatosis fetal ascites macrosomia and wilms tumor"}}], "symbols": [{"value": {"type": "Preferred", "value": "PRLMNS"}, "xrefs": [{"db": "OMIM", "id": "267000", "type": "MIM"}]}], "attributes": [{"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "3936"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301471"}, {"source": "BookShelf", "value": "NBK1294"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0009965"}, {"db": "MedGen", "id": "C0796113"}, {"db": "Orphanet", "id": "2849"}, {"db": "OMIM", "id": "267000", "type": "MIM"}]}], "id": 7919}, "date_created": "2018-05-28", "date_last_updated": "2022-04-23", "id": 1499499}, "record_status": "current", "title": "NC_000002.11:g.(?_233194517)_(233198703_?)dup AND Perlman syndrome", "clinvar_assertions": [{"id": 1469804, "submission_id": {"local_key": "2674743|MedGen:C0796113", "submitter": "Invitae", "submitted_assembly": "GRCh37", "submitter_date": "2018-04-02"}, "clinvar_accession": {"acc": "SCV000760069", "version": 1, "type": "SCV", "date_updated": "2018-05-28", "date_created": "2018-05-28", "org_id": "500031", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["uncertain significance"], "comments": [{"text": "This variant is a gross duplication of the genomic region encompassing exons 15-21 of the DIS3L2 gene. The 5' boundary is likely confined to intron 14. The 3' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. The exact location of this variant in the genome is unknown. Duplication of exons 15-21 has not been reported in the literature in individuals with DIS3L2-related disease. In summary, the exact genomic location of this variant is unknown and the impact of this duplication on DIS3L2 protein function has not been established. Therefore, it has been classified as a Variant of Uncertain Significance."}], "date_last_evaluated": "2017-09-13"}], "external_ids": [{"db": "Invitae", "id": "2674743"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "Invitae Variant Classification Sherloc (09022015)"}, "citations": [{"ids": [{"source": "PubMed", "value": "28492532"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NC_000002.11:g.(?_233194517)_(233198703_?)dup"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "DIS3L2"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "MedGen", "id": "C0796113", "type": "CUI"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000640484", "version": 3, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2018-05-28"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "pathogenic", "date_last_evaluated": "2018-08-14"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000533385", "version": 2, "measures": [{"type": "duplication", "names": [{"value": {"type": "Preferred", "value": "NC_000023.10:g.(?_103031893)_(103045546_?)dup"}}], "attributes": [{"type": "HGVS, genomic, top level, previous", "value": "NC_000023.10:g.(?_103031893)_(103045546_?)dup", "integer_value": 37}], "cytogenic_locations": ["Xq22.2"], "sequence_locations": [{"assembly": "GRCh37", "chr": "X", "accession": "NC_000023.10", "inner_start": 103031893, "inner_stop": 103045546, "display_start": 103031893, "display_stop": 103045546, "variant_length": 13654, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "proteolipid protein 1"}}], "symbols": [{"value": {"type": "Preferred", "value": "PLP1"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "X", "accession": "NC_000023.11", "start": 103776506, "stop": 103792619, "display_start": 103776506, "display_stop": 103792619, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "X", "accession": "NC_000023.10", "start": 103031438, "stop": 103047547, "display_start": 103031438, "display_stop": 103047547, "strand": "+", "variant_length": 16110, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "5354"}, {"db": "OMIM", "id": "300401", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:9086"}]}], "id": 534374}], "names": [{"value": {"type": "Preferred", "value": "NC_000023.10:g.(?_103031893)_(103045546_?)dup"}}], "id": 533385}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Hereditary spastic paraplegia 2"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0010733"}]}, {"value": {"type": "Alternate", "value": "SPASTIC PARAPLEGIA 2, X-LINKED"}, "xrefs": [{"db": "OMIM", "id": "312920", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Spastic paraplegia 2"}, "xrefs": [{"db": "Genetic Alliance", "id": "Spastic+paraplegia+2/6686"}]}], "symbols": [{"value": {"type": "Preferred", "value": "SPG2"}, "xrefs": [{"db": "OMIM", "id": "312920", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "SPPX2"}, "xrefs": [{"db": "OMIM", "id": "312920", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "PLP1 disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families. Heterozygous females may manifest mild-to-moderate signs of the disease."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1182"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "4923"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301361"}, {"source": "BookShelf", "value": "NBK1182"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0010733"}, {"db": "MedGen", "id": "C1839264"}, {"db": "Orphanet", "id": "99015"}, {"db": "OMIM", "id": "312920", "type": "MIM"}]}], "id": 3068}, "date_created": "2018-05-28", "date_last_updated": "2022-04-23", "id": 1501438}, "record_status": "current", "title": "NC_000023.10:g.(?_103031893)_(103045546_?)dup AND Hereditary spastic paraplegia 2", "clinvar_assertions": [{"id": 1471811, "submission_id": {"local_key": "1003803|MedGen:C1839264", "submitter": "Invitae", "submitted_assembly": "GRCh37", "submitter_date": "2019-03-28"}, "clinvar_accession": {"acc": "SCV000762076", "version": 3, "type": "SCV", "date_updated": "2019-08-13", "date_created": "2018-05-28", "org_id": "500031", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["pathogenic"], "citations": [{"ids": [{"source": "PubMed", "value": "10319885"}]}, {"ids": [{"source": "PubMed", "value": "9633722"}]}, {"ids": [{"source": "PubMed", "value": "8659540"}]}, {"ids": [{"source": "PubMed", "value": "23347225"}]}, {"ids": [{"source": "PubMed", "value": "10417279"}]}], "comments": [{"text": "A gross duplication of the genomic region encompassing the full coding sequence of the PLP1 gene has been identified. The boundaries of this event are unknown as the duplication extends beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this duplication is unknown, it may be in tandem or it may be located elsewhere in the genome. Duplication of PLP1 is clearly defined as a Pelizaeus-Merzbacher disease causative allele and is the most common cause of disease in affected individuals (PMID: 9633722, 10417279, 8659540, 10319885, 23347225). For these reasons, this variant has been classified as Pathogenic."}], "date_last_evaluated": "2018-08-14"}], "external_ids": [{"db": "Invitae", "id": "1003803"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "Invitae Variant Classification Sherloc (09022015)"}, "citations": [{"ids": [{"source": "PubMed", "value": "28492532"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NC_000023.10:g.(?_103031893)_(103045546_?)dup"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "PLP1"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "Spastic paraplegia 2"}}], "xrefs": [{"db": "MedGen", "id": "C1839264", "type": "CUI"}]}]}, "citations": [{"ids": [{"source": "PubMed", "value": "28492532"}], "type": "general"}]}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000000235", "version": 4, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "1996-11-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In an individual with prolidase deficiency (170100) who was asymptomatic at age 11 years, Ledoux et al. (1996) demonstrated compound heterozygosity for a G-to-A transition at nucleotide 551 in exon 8 (R184Q) and a G-to-A transition of nucleotide 833 in exon 123 (G278D; 613230.0004) in the PEPD gene. To assess the biochemical phenotypes of these and 2 previously identified PEPD mutations (G448R, 613230.0005 and E452DEL, 613230.0006), they designed a transient expression system for prolidase in COS-1 cells. The enzyme was expressed as a fusion protein carrying an N-terminal tag, allowing its immunologic discrimination from the endogenous enzyme with a monoclonal antibody. Expression of the R184Q mutation produced 7.4% of control enzymatic activity, whereas the expression of the other 3 mutations produced inactive enzymes. Western analysis of the R184Q, G278D, and G448R prolidases revealed stable immunoreactive material whereas the E452DEL prolidase was not detectable. Pulse-chase metabolic labeling of cells followed by immunoprecipitation revealed that the E452DEL mutant protein was synthesized but had an increased rate of degradation."}, "citations": [{"ids": [{"source": "PubMed", "value": "8900231"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000000211", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_000285.4(PEPD):c.551G>A (p.Arg184Gln)"}}], "canonical_spdi": "NC_000019.10:33464059:C:T", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001166057.2:c.359G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001166056.2:c.548+13986G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000285.4:c.551G>A"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_013358.1:g.62834G>A"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_013358.2:g.62834G>A"}, {"type": "HGVS, genomic, top level", "value": "NC_000019.10:g.33464060C>T", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000019.9:g.33954966C>T", "integer_value": 37}, {"type": "HGVS, protein", "value": "P12955:p.Arg184Gln"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001159529.1:p.Arg120Gln"}, {"type": "HGVS, protein, RefSeq", "value": "NP_000276.2:p.Arg184Gln"}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001166056.2:c.548+13986G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_000285.4:c.551G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001166057.2:c.359G>A"}]}, {"type": "ProteinChange1LetterCode", "value": "R120Q"}, {"type": "ProteinChange1LetterCode", "value": "R184Q"}, {"type": "ProteinChange3LetterCode", "value": "ARG184GLN"}], "cytogenic_locations": ["19q13.11"], "sequence_locations": [{"assembly": "GRCh38", "chr": "19", "accession": "NC_000019.10", "start": 33464060, "stop": 33464060, "display_start": 33464060, "display_stop": 33464060, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 33464060, "reference_allele_vcf": "C", "alternate_allele_vcf": "T"}, {"assembly": "GRCh37", "chr": "19", "accession": "NC_000019.9", "start": 33954966, "stop": 33954966, "display_start": 33954966, "display_stop": 33954966, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 33954966, "reference_allele_vcf": "C", "alternate_allele_vcf": "T"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "peptidase D"}}], "symbols": [{"value": {"type": "Preferred", "value": "PEPD"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "19", "accession": "NC_000019.10", "start": 33386950, "stop": 33521791, "display_start": 33386950, "display_stop": 33521791, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "19", "accession": "NC_000019.9", "start": 33877854, "stop": 34012798, "display_start": 33877854, "display_stop": 34012798, "strand": "-", "variant_length": 134945, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "5184"}, {"db": "OMIM", "id": "613230", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:8840"}]}], "xrefs": [{"db": "UniProtKB", "id": "P12955#VAR_011614"}, {"db": "OMIM", "id": "613230.0003", "type": "Allelic variant"}, {"db": "dbSNP", "id": "121917722", "type": "rs"}], "id": 15250}], "names": [{"value": {"type": "Preferred", "value": "NM_000285.4(PEPD):c.551G>A (p.Arg184Gln)"}}], "xrefs": [{"db": "ClinGen", "id": "CA214913"}], "id": 211}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Prolidase deficiency"}, "xrefs": [{"db": "Genetic Alliance", "id": "Prolidase+deficiency/5991"}, {"db": "MONDO", "id": "MONDO:0008221"}]}], "attributes": [{"value": {"type": "public definition", "value": "Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and hepatomegaly with elevated liver enzymes and splenomegaly. Anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are common. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described."}, "xrefs": [{"db": "GeneReviews", "id": "NBK299584"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "7473"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "26110198"}, {"source": "BookShelf", "value": "NBK299584"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0008221"}, {"db": "MedGen", "id": "C0268532"}, {"db": "Orphanet", "id": "742"}, {"db": "OMIM", "id": "170100", "type": "MIM"}]}], "id": 70}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 57738}, "record_status": "current", "title": "NM_000285.4(PEPD):c.551G>A (p.Arg184Gln) AND Prolidase deficiency", "clinvar_assertions": [{"id": 20379, "submission_id": {"local_key": "613230.0003_PROLIDASE DEFICIENCY", "submitter": "OMIM", "title": "PEPD, ARG184GLN_PROLIDASE DEFICIENCY", "submitter_date": "2015-05-12"}, "clinvar_accession": {"acc": "SCV000020379", "version": 2, "type": "SCV", "date_updated": "2015-05-18", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "1996-11-01"}], "external_ids": [{"db": "OMIM", "id": "613230.0003", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In an individual with prolidase deficiency (170100) who was asymptomatic at age 11 years, Ledoux et al. (1996) demonstrated compound heterozygosity for a G-to-A transition at nucleotide 551 in exon 8 (R184Q) and a G-to-A transition of nucleotide 833 in exon 123 (G278D; 613230.0004) in the PEPD gene. To assess the biochemical phenotypes of these and 2 previously identified PEPD mutations (G448R, 613230.0005 and E452DEL, 613230.0006), they designed a transient expression system for prolidase in COS-1 cells. The enzyme was expressed as a fusion protein carrying an N-terminal tag, allowing its immunologic discrimination from the endogenous enzyme with a monoclonal antibody. Expression of the R184Q mutation produced 7.4% of control enzymatic activity, whereas the expression of the other 3 mutations produced inactive enzymes. Western analysis of the R184Q, G278D, and G448R prolidases revealed stable immunoreactive material whereas the E452DEL prolidase was not detectable. Pulse-chase metabolic labeling of cells followed by immunoprecipitation revealed that the E452DEL mutant protein was synthesized but had an increased rate of degradation."}, "citations": [{"ids": [{"source": "PubMed", "value": "8900231"}]}], "xrefs": [{"db": "OMIM", "id": "170100", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "PEPD, ARG184GLN"}}], "attributes": [{"type": "NonHGVS", "value": "ARG184GLN"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "PEPD"}}]}], "xrefs": [{"db": "OMIM", "id": "613230.0003", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "PROLIDASE DEFICIENCY"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000001241", "version": 3, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2001-09-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Hampf et al. (2001) reported a case of steroid 11-beta-hydroxylase deficiency (202010) caused by an unequal crossover of the genes encoding aldosterone synthase (CYP11B2; 124080) and 11-beta-hydroxylase (CYP11B1). CYP11B1 and CYP11B2 are located on chromosome 8q24 approximately 45 kb apart from each other. The investigated genetic recombination deleted the normal alleles of the 2 genes and created a chimeric fusion gene, which consists of the promoter and exons 1 through 4 of the CYP11B2 gene plus intron 4 through exon 9 of the CYP11B1 gene. This recombination event subordinated any remaining CYP11B1 activity of the chimeric enzyme to the control mechanisms of CYP11B2, the expression of which is mainly regulated by angiotensin II (see 106150) and potassium. Normally the CYP11B1 activity is controlled by ACTH. Furthermore, by applying a minigene expression method, Hampf et al. (2001) demonstrated a point mutation in intron 3 (IVS3+16G-T; 610613.0013) of the patient's second CYP11B1 allele that radically diminished proper splicing of the pre-mRNA by giving rise to a new, highly preferred donor splice site."}, "citations": [{"ids": [{"source": "PubMed", "value": "11549691"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000001182", "version": 2, "measures": [{"type": "deletion", "names": [{"value": {"type": "Preferred", "value": "CYP11B1, CYP11B1/CYP11B2 CHIMERA"}}, {"value": {"type": "Alternate", "value": "CYP11B1, CYP11B1/CYP11B2 CHIMERA"}, "xrefs": [{"db": "OMIM", "id": "610613.0012", "type": "Allelic variant"}]}], "cytogenic_locations": ["8q21"], "measure_relationship": [{"type": "asserted, but not computed", "names": [{"value": {"type": "Preferred", "value": "cytochrome P450 family 11 subfamily B member 1"}}], "symbols": [{"value": {"type": "Preferred", "value": "CYP11B1"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "8", "accession": "NC_000008.11", "start": 142872357, "stop": 142879825, "display_start": 142872357, "display_stop": 142879825, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "8", "accession": "NC_000008.10", "start": 143953772, "stop": 143961235, "display_start": 143953772, "display_stop": 143961235, "strand": "-", "variant_length": 7464, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "1584"}, {"db": "OMIM", "id": "610613", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:2591"}]}], "xrefs": [{"db": "OMIM", "id": "610613.0012", "type": "Allelic variant"}], "id": 16221}], "names": [{"value": {"type": "Preferred", "value": "CYP11B1, CYP11B1/CYP11B2 CHIMERA"}}], "id": 1182}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Deficiency of steroid 11-beta-monooxygenase"}, "xrefs": [{"db": "Genetic Alliance", "id": "Deficiency+of+steroid+11-beta-monooxygenase/8204"}, {"db": "SNOMED CT", "id": "124214007"}]}, {"value": {"type": "Alternate", "value": "ADRENAL HYPERPLASIA, CONGENITAL, DUE TO STEROID 11-BETA-HYDROXYLASE DEFICIENCY"}, "xrefs": [{"db": "OMIM", "id": "202010", "type": "MIM"}, {"db": "OMIM", "id": "610613.0001", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0003", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0004", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0005", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0006", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0007", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0008", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0009", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0010", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0011", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0012", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0013", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0014", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0015", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0016", "type": "Allelic variant"}, {"db": "OMIM", "id": "610613.0017", "type": "Allelic variant"}]}, {"value": {"type": "Alternate", "value": "11-beta-hydroxylase deficiency"}}, {"value": {"type": "Alternate", "value": "Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0008729"}]}, {"value": {"type": "Alternate", "value": "Adrenal hyperplasia IV"}}, {"value": {"type": "Alternate", "value": "Adrenal hyperplasia 4"}}, {"value": {"type": "Alternate", "value": "Steroid 11-beta-hydroxylase deficiency"}}, {"value": {"type": "Alternate", "value": "11-alpha beta-hydroxylase deficiency"}}, {"value": {"type": "Alternate", "value": "Adrenal hyperplasia hypertensive form"}}, {"value": {"type": "Alternate", "value": "P450c11b1 deficiency"}}], "symbols": [{"value": {"type": "Preferred", "value": "CYP11B1"}}], "attributes": [{"value": {"type": "disease mechanism", "value": "loss of function"}, "xrefs": [{"db": "Genetic Testing Registry (GTR)", "id": "GTR000506354"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000508723"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000528276"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000556817"}, {"db": "Genetic Testing Registry (GTR)", "id": "GTR000556819"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "5658"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0008729"}, {"db": "MedGen", "id": "C0268292"}, {"db": "OMIM", "id": "202010", "type": "MIM"}]}], "id": 312}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 58744}, "record_status": "current", "title": "CYP11B1, CYP11B1/CYP11B2 CHIMERA AND Deficiency of steroid 11-beta-monooxygenase", "clinvar_assertions": [{"id": 21391, "submission_id": {"local_key": "610613.0012_ADRENAL HYPERPLASIA, CONGENITAL, DUE TO STEROID 11-BETA-HYDROXYLASE DEFICIENCY", "submitter": "OMIM", "title": "CYP11B1, CYP11B1/CYP11B2 CHIMERA_ADRENAL HYPERPLASIA, CONGENITAL, DUE TO STEROID 11-BETA-HYDROXYLASE DEFICIENCY", "submitter_date": "2022-02-22"}, "clinvar_accession": {"acc": "SCV000021391", "version": 2, "type": "SCV", "date_updated": "2022-02-26", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2001-09-01"}], "external_ids": [{"db": "OMIM", "id": "610613.0012", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Hampf et al. (2001) reported a case of steroid 11-beta-hydroxylase deficiency (202010) caused by an unequal crossover of the genes encoding aldosterone synthase (CYP11B2; 124080) and 11-beta-hydroxylase (CYP11B1). CYP11B1 and CYP11B2 are located on chromosome 8q24 approximately 45 kb apart from each other. The investigated genetic recombination deleted the normal alleles of the 2 genes and created a chimeric fusion gene, which consists of the promoter and exons 1 through 4 of the CYP11B2 gene plus intron 4 through exon 9 of the CYP11B1 gene. This recombination event subordinated any remaining CYP11B1 activity of the chimeric enzyme to the control mechanisms of CYP11B2, the expression of which is mainly regulated by angiotensin II (see 106150) and potassium. Normally the CYP11B1 activity is controlled by ACTH. Furthermore, by applying a minigene expression method, Hampf et al. (2001) demonstrated a point mutation in intron 3 (IVS3+16G-T; 610613.0013) of the patient's second CYP11B1 allele that radically diminished proper splicing of the pre-mRNA by giving rise to a new, highly preferred donor splice site."}, "citations": [{"ids": [{"source": "PubMed", "value": "11549691"}]}], "xrefs": [{"db": "OMIM", "id": "202010", "type": "MIM"}, {"db": "OMIM", "id": "124080", "type": "MIM"}, {"db": "OMIM", "id": "106150", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "CYP11B1, CYP11B1/CYP11B2 CHIMERA"}}], "attributes": [{"type": "NonHGVS", "value": "CYP11B1/CYP11B2 CHIMERA"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "CYP11B1"}}]}], "xrefs": [{"db": "OMIM", "id": "610613.0012", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "ADRENAL HYPERPLASIA, CONGENITAL, DUE TO STEROID 11-BETA-HYDROXYLASE DEFICIENCY"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000001288", "version": 5, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2006-10-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Topaz et al. (2006) identified homozygosity for a c.4483A-G transition in the SAMD9 gene, resulting in a lys1495-to-glu (K1495E) substitution, as the cause of normophosphatemic familial tumoral calcinosis (NFTC; 610455) in 5 Jewish Yemenite families. The K1495E mutation caused loss of punctate expression of a GFP-SAMD9 fusion protein after transfection in HEK293 cells, indicating that this mutation interferes with SAMD9 expression. In a screening of 92 healthy, unrelated Jewish individuals born to couples who immigrated to Israel from Yemen, Topaz et al. (2006) found 1 individual who carried both K1495E and the disease haplotype in the heterozygous state, which corresponded to a carrier rate of approximately 0.01, fitting the expected prevalence of the disease in the Israeli Jewish Yemenite population."}, "citations": [{"ids": [{"source": "PubMed", "value": "16960814"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000001229", "version": 3, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_017654.4(SAMD9):c.4483A>G (p.Lys1495Glu)"}}], "canonical_spdi": "NC_000007.14:93101614:T:C", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001193307.2:c.4483A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_017654.4:c.4483A>G"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_023419.1:g.21409A>G"}, {"type": "HGVS, genomic, top level", "value": "NC_000007.14:g.93101615T>C", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000007.13:g.92730928T>C", "integer_value": 37}, {"type": "HGVS, protein", "value": "Q5K651:p.Lys1495Glu"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001180236.1:p.Lys1495Glu"}, {"type": "HGVS, protein, RefSeq", "value": "NP_060124.2:p.Lys1495Glu"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001193307.2:c.4483A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_017654.4:c.4483A>G"}]}, {"type": "ProteinChange1LetterCode", "value": "K1495E"}, {"type": "ProteinChange3LetterCode", "value": "LYS1495GLU"}], "cytogenic_locations": ["7q21.2"], "sequence_locations": [{"assembly": "GRCh38", "chr": "7", "accession": "NC_000007.14", "start": 93101615, "stop": 93101615, "display_start": 93101615, "display_stop": 93101615, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 93101615, "reference_allele_vcf": "T", "alternate_allele_vcf": "C"}, {"assembly": "GRCh37", "chr": "7", "accession": "NC_000007.13", "start": 92730928, "stop": 92730928, "display_start": 92730928, "display_stop": 92730928, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 92730928, "reference_allele_vcf": "T", "alternate_allele_vcf": "C"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "sterile alpha motif domain containing 9"}}], "symbols": [{"value": {"type": "Preferred", "value": "SAMD9"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "7", "accession": "NC_000007.14", "start": 93099518, "stop": 93117979, "display_start": 93099518, "display_stop": 93117979, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "7", "accession": "NC_000007.13", "start": 92728825, "stop": 92747335, "display_start": 92728825, "display_stop": 92747335, "strand": "-", "variant_length": 18511, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "54809"}, {"db": "OMIM", "id": "610456", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:1348"}]}], "xrefs": [{"db": "UniProtKB", "id": "Q5K651#VAR_031529"}, {"db": "OMIM", "id": "610456.0001", "type": "Allelic variant"}, {"db": "dbSNP", "id": "121918554", "type": "rs"}], "id": 16268}], "names": [{"value": {"type": "Preferred", "value": "NM_017654.4(SAMD9):c.4483A>G (p.Lys1495Glu)"}}], "xrefs": [{"db": "ClinGen", "id": "CA114859"}], "id": 1229}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Normophosphatemic familial tumoral calcinosis"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0012502"}]}, {"value": {"type": "Alternate", "value": "CALCINOSIS, TUMORAL, WITH NORMOPHOSPHATEMIA"}, "xrefs": [{"db": "OMIM", "id": "610455", "type": "MIM"}]}], "symbols": [{"value": {"type": "Alternate", "value": "NFTC"}, "xrefs": [{"db": "OMIM", "id": "610455", "type": "MIM"}]}], "attributes": [{"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "10878"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0012502"}, {"db": "MedGen", "id": "C1864861"}, {"db": "Orphanet", "id": "53715"}, {"db": "OMIM", "id": "610455", "type": "MIM"}]}], "id": 6660}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 58791}, "record_status": "current", "title": "NM_017654.4(SAMD9):c.4483A>G (p.Lys1495Glu) AND Normophosphatemic familial tumoral calcinosis", "clinvar_assertions": [{"id": 21438, "submission_id": {"local_key": "610456.0001_TUMORAL CALCINOSIS, NORMOPHOSPHATEMIC, FAMILIAL", "submitter": "OMIM", "title": "SAMD9, LYS1495GLU_TUMORAL CALCINOSIS, NORMOPHOSPHATEMIC, FAMILIAL", "submitter_date": "2020-06-22"}, "clinvar_accession": {"acc": "SCV000021438", "version": 4, "type": "SCV", "date_updated": "2020-06-26", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2006-10-01"}], "external_ids": [{"db": "OMIM", "id": "610456.0001", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Topaz et al. (2006) identified homozygosity for a c.4483A-G transition in the SAMD9 gene, resulting in a lys1495-to-glu (K1495E) substitution, as the cause of normophosphatemic familial tumoral calcinosis (NFTC; 610455) in 5 Jewish Yemenite families. The K1495E mutation caused loss of punctate expression of a GFP-SAMD9 fusion protein after transfection in HEK293 cells, indicating that this mutation interferes with SAMD9 expression. In a screening of 92 healthy, unrelated Jewish individuals born to couples who immigrated to Israel from Yemen, Topaz et al. (2006) found 1 individual who carried both K1495E and the disease haplotype in the heterozygous state, which corresponded to a carrier rate of approximately 0.01, fitting the expected prevalence of the disease in the Israeli Jewish Yemenite population."}, "citations": [{"ids": [{"source": "PubMed", "value": "16960814"}]}], "xrefs": [{"db": "OMIM", "id": "610455", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "SAMD9, LYS1495GLU"}}], "attributes": [{"type": "NonHGVS", "value": "LYS1495GLU"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "SAMD9"}}]}], "xrefs": [{"db": "OMIM", "id": "610456.0001", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "TUMORAL CALCINOSIS, NORMOPHOSPHATEMIC, FAMILIAL"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000005355", "version": 4, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2000-08-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "somatic", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a leukemic cells derived from a patient with juvenile myelomonocytic leukemia (JMML; 607785) and a fusion between the MLL gene on 11q and the GRAF gene on 5q, Borkhardt et al. (2000) identified in the other GRAF allele an A-to-G transition at nucleotide 1255 that resulted in the substitution of a serine for an asparagine at amino acid 417. This was thought to be a second hit in a leukemogenic process."}, "citations": [{"ids": [{"source": "PubMed", "value": "10908648"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000005052", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_001135608.3(ARHGAP26):c.1250A>G (p.Asn417Ser)"}}], "canonical_spdi": "NC_000005.10:143041854:A:G", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_1127t1:c.1250A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001349547.2:c.1142A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001135608.3:c.1250A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_015071.6:c.1250A>G"}, {"type": "HGVS, genomic, LRG", "value": "LRG_1127:g.276486A>G"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_016711.2:g.276486A>G"}, {"type": "HGVS, genomic, top level", "value": "NC_000005.10:g.143041855A>G", "integer_value": 38}, {"type": "HGVS, genomic, top level, 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{"db": "HGNC", "id": "HGNC:17073"}]}], "xrefs": [{"db": "UniProtKB", "id": "Q9UNA1#VAR_013623"}, {"db": "OMIM", "id": "605370.0001", "type": "Allelic variant"}, {"db": "dbSNP", "id": "121918546", "type": "rs"}], "id": 20091}], "names": [{"value": {"type": "Preferred", "value": "NM_001135608.3(ARHGAP26):c.1250A>G (p.Asn417Ser)"}}], "xrefs": [{"db": "ClinGen", "id": "CA117231"}], "id": 5052}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Juvenile myelomonocytic leukemia"}, "xrefs": [{"db": "Genetic Alliance", "id": "Juvenile+Myelomonocytic+Leukemia+%28JMML%29/3936"}, {"db": "Human Phenotype Ontology", "id": "HP:0012209"}, {"db": "MONDO", "id": "MONDO:0011908"}]}, {"value": {"type": "Alternate", "value": "LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC"}, "xrefs": [{"db": "OMIM", "id": "176876.0014", "type": "Allelic variant"}, {"db": "OMIM", "id": "176876.0015", "type": "Allelic variant"}, {"db": "OMIM", "id": "176876.0016", "type": "Allelic variant"}, {"db": "OMIM", "id": "176876.0017", "type": "Allelic variant"}, {"db": "OMIM", "id": "605370.0001", "type": "Allelic variant"}, {"db": "OMIM", "id": "605370.0002", "type": "Allelic variant"}, {"db": "OMIM", "id": "605370.0003", "type": "Allelic variant"}]}], "symbols": [{"value": {"type": "Preferred", "value": "JMML"}, "xrefs": [{"db": "OMIM", "id": "607785", "type": "MIM"}]}], "attributes": [{"value": {"type": "keyword", "value": "Hereditary cancer syndrome"}}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "9884"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "24493721"}], "type": "practice guideline", "abbrev": "ASCO, 2014"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0011908"}, {"db": "MedGen", "id": "C0349639"}, {"db": "Orphanet", "id": "86834"}, {"db": "OMIM", "id": "607785", "type": "MIM"}, {"db": "Human Phenotype Ontology", "id": "HP:0012209", "type": "primary"}]}], "id": 99}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 62858}, "record_status": "current", "title": "NM_001135608.3(ARHGAP26):c.1250A>G (p.Asn417Ser) AND Juvenile myelomonocytic leukemia", "clinvar_assertions": [{"id": 25533, "submission_id": {"local_key": "605370.0001_LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC", "submitter": "OMIM", "title": "ARHGAP26, ASN417SER_LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC", "submitter_date": "2011-05-19"}, "clinvar_accession": {"acc": "SCV000025533", "version": 1, "type": "SCV", "date_updated": "2013-04-04", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2000-08-01"}], "external_ids": [{"db": "OMIM", "id": "605370.0001", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "somatic", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a leukemic cells derived from a patient with juvenile myelomonocytic leukemia (JMML; 607785) and a fusion between the MLL gene on 11q and the GRAF gene on 5q, Borkhardt et al. (2000) identified in the other GRAF allele an A-to-G transition at nucleotide 1255 that resulted in the substitution of a serine for an asparagine at amino acid 417. This was thought to be a second hit in a leukemogenic process."}, "citations": [{"ids": [{"source": "PubMed", "value": "10908648"}]}], "xrefs": [{"db": "OMIM", "id": "607785", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "ARHGAP26, ASN417SER"}}], "attributes": [{"type": "NonHGVS", "value": "ASN417SER"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "ARHGAP26"}}]}], "xrefs": [{"db": "OMIM", "id": "605370.0001", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000006031", "version": 5, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2007-12-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In affected individuals of a large Brazilian kindred with spastic paraplegia-4 (SPG4; 182601), originally reported by Starling et al. (2002), Mitne-Neto et al. (2007) identified a heterozygous tandem duplication of exons 10 through 12 of the SPAST gene. Long-range PCR and sequencing showed nonhomology of the sequences contributing to the novel fusion. The duplication was predicted to result in premature termination and disruption of enzymatic activity. Twelve of 30 mutation carriers had no clinical complaints. Among these patients, 9 of 14 female carriers had no complaints, indicating sex-dependent penetrance in this family, with women being partially protected."}, "citations": [{"ids": [{"source": "PubMed", "value": "12471215"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": "17895902"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000005677", "version": 3, "measures": [{"type": "duplication", "names": [{"value": {"type": "Preferred", "value": "NM_014946.4(SPAST):c.1246-2896_1493+523dup"}}, {"value": {"type": "Alternate", "value": "SPAST, EX10-12DUP"}, "xrefs": [{"db": "OMIM", "id": "604277.0022", "type": "Allelic variant"}]}], "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001363875.2:c.1147-2896_1394+523dup"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001377959.1:c.1150-2896_1397+523dup"}, {"type": "HGVS, coding, RefSeq", "value": "NM_199436.2:c.1150-2896_1397+523dup"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001363823.2:c.1243-2896_1490+523dup"}, {"type": "HGVS, coding, RefSeq", "value": "NM_014946.4:c.1246-2896_1493+523dup"}, {"type": "HGVS, genomic, LRG", "value": "LRG_714:g.75057_79101dup"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_008730.1:g.75057_79101dup"}, {"type": "HGVS, genomic, top level", "value": "NC_000002.12:g.32133667_32137711dup", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000002.11:g.32358736_32362780dup", "integer_value": 37}, {"type": "HGVS, protein"}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001363823.2:c.1243-2896_1490+523dup"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001363875.2:c.1147-2896_1394+523dup"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001377959.1:c.1150-2896_1397+523dup"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_014946.4:c.1246-2896_1493+523dup"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_199436.2:c.1150-2896_1397+523dup"}]}, {"type": "MolecularConsequence", "value": "splice donor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001575"}, {"db": "RefSeq", "id": "NM_001363823.2:c.1243-2896_1490+523dup"}]}, {"type": "MolecularConsequence", "value": "splice donor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001575"}, {"db": "RefSeq", "id": "NM_001363875.2:c.1147-2896_1394+523dup"}]}, {"type": "MolecularConsequence", "value": "splice donor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001575"}, {"db": "RefSeq", "id": "NM_001377959.1:c.1150-2896_1397+523dup"}]}, {"type": "MolecularConsequence", "value": "splice donor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001575"}, {"db": "RefSeq", "id": "NM_014946.4:c.1246-2896_1493+523dup"}]}, {"type": "MolecularConsequence", "value": "splice donor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001575"}, {"db": "RefSeq", "id": "NM_199436.2:c.1150-2896_1397+523dup"}]}], "cytogenic_locations": ["2p22.3"], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 32133666, "stop": 32133667, "display_start": 32133666, "display_stop": 32133667, "variant_length": 4045, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 32133666, "reference_allele_vcf": "A", "alternate_allele_vcf": "AAACGAACATTCACATAGTTCTTACCAGTTTACAGTGTTTTTTCCACACCGTCTTCAAAATGTAAAGTTTGGTCTTCAATACATCAGTATGCTGCTAGATTTAAATACTAGGGAAAAAAAAATCAGAGAAGTTAATAATATTAACTGTCACCTCCACTAGAAGATGGTCTCCATGTGGACAGTAATATTTCTCTTGTATTATCTGTGCTAAGTAAAATCTTCTGTAAGTTTCTTTAAATATTTTAATAAATCATAGTACTTAAAATGTTCTCAATATTCTAAAGTAGTTAAAAGTAACTATAAAATAGTACCTGTTTTTCTGATCACATTTTACTTCCTATGTGAAATTTTACAAGTCGTTACTCTATTTATTTATTGATTTATTTTTTAAGACAGGGTCTGTTCTGTCGCCCAGGCTGGAGTACAGTGGCGTGATCATGGCTCACTGCAGCCTCAGCCTCCTGGGCTCAAGTGATCCTCCCACCTTAGCATCCCAAGTAGCTGGGACTATAGGCACATGCCACCATGCCCAGCTAATTTTAAAAAATTCTGGGGGGCCGAATGCGGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCCGAGGCAGGCGAATCACAAGGTCAGGAGTTCGAGACCAGCCTGGCTAACATGGTGAAACCCTGTCTCTACTAAAAATACAAAAAATTAGCGGGGTGTGGTGGCAGGCGCCTGTAATCCCACTTACTCAGGAGGCTGAGGCAGGAGAGTTGCTTGAACCTGGGAGGCAGAGATTGCAGTGAGCCGAGACTCCATCTCAAAAAAAAAAAATTTTTTTTTGTAGTGACAAGGTGTCACTGTGTTGCCAGGGCTGGTCTCAAACTTCTGGGCTCAAGTGATCCTCCCATTTCGGCCTCCCAAAGTGCTAGGATCACAGGCATGAGTCACTGTGCCTGGTCTTCAAGTTGTTATTAAAGCATGTTTACCCACATTATGCACATGGTATAATGGAAAGTATTGTTGTGGAAGTTAGGAGATAGGGATTCTAGCCTAGCTTTTTATTTTTTTGGGACAAGGTCTCACTTTTTCGCCCCAGGCCGAAGTGCAGTTGTGCGATCTCGGCTCACTGCAACCTCCAACTCTCAGGTTCAAGCAATTCTCCCACGTCAGCCTCCCGAGTAGCTGGGATTACAGGCATGCGCCACCACGCCCGGCTAATTTTTGTAGTTTTAGTAGACACAGGGTTTCACCATGTTGGCCAGGCTGGTCTTGAACTCCCGACCTCAGGTGATCCACCCACCTTGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACCGCACCCGGCCTCTAGCGTAACTTTTACATCCTGAACTGACCTTAAGAAAGTATAACTTTAGGCCTGTTTCATCTGTAAAATGTTAATGTCATAGGAGATGATCTTTTGAGATTTCTTTCAGCTCTGATAATTTTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGAGATGGAGTCTTGCTCTGTCGCCCGGGCTGGAGTGCAGTGGTACCATCTCGGCTCACTGCAAGCTCCACCTCCTGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTACAGGCGCCTGCCACCACGCCTGGCTAATTTTTTGTATTTTTAGTAGAGACGAGGTTTCACCGTGTTAGCCAGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCAGCCTCCCAAAGTGCTGGGATTACAGGTCTGAGCCGCCGCGCCCGGCCTAGAATATTTGTTTCGATTATTCTAAATCTGGTGACATTTCTTTTGTTTTTAAGTTAAATCTTCAGTAAAAAGAATAAATGCCACCTAGAGGACAGAAAAATTTTTACAGTAGATTATCACAGACCTCATGACTCATTACTTTGGTGTATAAAATGGCCTTTGTATGGTGTCAGCACCTGGGAATGTCTCAAGGGGTGTTCATTGACCTTCTGGACTATCTGGAAATATTTTGATATTTATTGGCTGGGCGCGGTGGCTCATGCCTGTAATTCCAGCACCTCGGGAGGCCAAGTTAGGTGGATCACTTGAGGTCAGGAGTTTGAGATCAGCCTGGCCAACTAAGTTAGTTGACTATTTGTGAAATTTCCCTCTCCAAATAGGAAAGATAGGATTGGAAACATTATTCAGAAGGAAGAAGTTTTAAAGAAGGGCAGGCTTAAAGACTATCTAATGAATTTACCAATATGGTAAAACCCCATCTTTACTAAAAATACAAAAATTAGCCAGGCGTGGTGGTGGGCGCCTGTAATCCCAGCTACCTGGGATGTTGAGGGATGAGAATCACTTGAACCCAGGAGGCAAAAGTCACAGTGAGCCGAGATTGCACCACTGCACTCCAGACTGGGCTATAGAGCAAAACTCTGTCTCAAAAAAAAAAAGGAAAAAAAAAAAAGAAATTTTGATATTTATGTGAGAATGACTTTTCACGGTGTTCTTAATAGCGCAAGTTTTGTTTAGGAGAGCACATTCCAACTTACTTGCTTCTATAAATATACCGTGTAATCTAGGGCTTAAAGAATATGTACAATGTCTTTTTCTCTCCCCTAGTCTTCCCCTTTTCTCACTAGTTATATCCTTGACTGAAGAGCTATTTCATTCTCAAGTCTTAGGAATGCAGGGTGAAGCAAAACAGATGAATTTTTAAAGCACTTAACCAGGCTGTATGAAATCACAGTCTGTTGTCTAAAATTGTAAGGGACGGTTAGTAGTACTCTCCCCTTTCTCAAACCAAATCTTTGGTTGTTTTAAGGAAGGGAAATTAAATTCCTGTGTGCTAGATTTTCAACATAAAATTTAAAAAACTGGAATAATGTTGCATTTTATGTGTATAACAGTATAATGCTTTGTTTTAGGTGGGAGAAGGAGAGAAATTGGTGAGGGCTCTTTTTGCTGTGGCTCGAGAACTTCAACCTTCTATAATTTTTATAGGTAAGAACATATTTTCCAACTAAGTTATTGACTATTTGTGAAATTTCCCTCTCCAAATAGGAAAGATACGATTGGAAACATTATTCAGAAGGAAGAAGTTTTAAAGAAGGGCAAGCTTAAAGACTATCTAATGAATTTAGTAGGACCCACTATATTAATAAGTAGTAAACTAGATTAATCTCAGATGACTCACATAGCTTGGTCTTTAATTAAAGTCTTATACTTGTATTTCCTCTAGATGAAGTTGATAGCCTTTTGTGTGAAAGAAGAGAAGGGGAGCACGATGCTAGTAGACGCCTAAAAACTGAATTTCTAATAGAATTTGATGGTGTAAGTGTTGATTATGATATTTTTAATGTGGCAGCATTTTAGTATATTTTCCTATTAAATGGCCAAGGTTAAAAATACAAATATCTTTATATTTGTTATTACTTTTCTAAATGAATTGAAAAAAGATTTTTTGCTTGTAGGTACAGTCTGCTGGAGATGACAGAGTACTTGTAATGGGTGCAACTAATAGGCCACAAGAGCTTGATGAGGCTGTTCTCAGGTAGGGAGATTTATATGGAAATACATGCATTTATTACAGACAATATTTACTCATGTGTCCATCTTACATATTATTTCCTTACTCTCAGTTTTAAGACTAAATTCACTATTTTCTTCCAGTACTATCTCTAGCCTCTTGTTACCAACTACATAAGGATTTTGAGGTCAACAGCTTGATATCAGGAGAATTAGTCTAGTAAAGGTTTAGTTACGGTTTTAGGCAAATTGGTCAGTTCTTCTGGGTTGCATTAAATTATCTTTAAACTTGAAAATTGATTCTTACCGTCTTTTATTGGGCTTCATGAGAAAATAATCAAATCAGGGTTCATGGAAAATGTGTTTTCTGTTCTTGTGTGTTTGAGCAGTTTATTCCCTTCATACTGGAAGGACGGTTTGGGTCAGCATAAAATTCTTGGGCATCCTTTCCCAAGGAATTTACAATATTGCTCCATTGTTTCTAGATTGGCTGTAGTAGTGTAAAAGTCTGAATCCAAATTGATTTTTTCAAATTTGTAAAATAACTT"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 32358735, "stop": 32358736, "display_start": 32358735, "display_stop": 32358736, "variant_length": 4045, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 32358735, "reference_allele_vcf": "A", "alternate_allele_vcf": "AAACGAACATTCACATAGTTCTTACCAGTTTACAGTGTTTTTTCCACACCGTCTTCAAAATGTAAAGTTTGGTCTTCAATACATCAGTATGCTGCTAGATTTAAATACTAGGGAAAAAAAAATCAGAGAAGTTAATAATATTAACTGTCACCTCCACTAGAAGATGGTCTCCATGTGGACAGTAATATTTCTCTTGTATTATCTGTGCTAAGTAAAATCTTCTGTAAGTTTCTTTAAATATTTTAATAAATCATAGTACTTAAAATGTTCTCAATATTCTAAAGTAGTTAAAAGTAACTATAAAATAGTACCTGTTTTTCTGATCACATTTTACTTCCTATGTGAAATTTTACAAGTCGTTACTCTATTTATTTATTGATTTATTTTTTAAGACAGGGTCTGTTCTGTCGCCCAGGCTGGAGTACAGTGGCGTGATCATGGCTCACTGCAGCCTCAGCCTCCTGGGCTCAAGTGATCCTCCCACCTTAGCATCCCAAGTAGCTGGGACTATAGGCACATGCCACCATGCCCAGCTAATTTTAAAAAATTCTGGGGGGCCGAATGCGGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCCGAGGCAGGCGAATCACAAGGTCAGGAGTTCGAGACCAGCCTGGCTAACATGGTGAAACCCTGTCTCTACTAAAAATACAAAAAATTAGCGGGGTGTGGTGGCAGGCGCCTGTAATCCCACTTACTCAGGAGGCTGAGGCAGGAGAGTTGCTTGAACCTGGGAGGCAGAGATTGCAGTGAGCCGAGACTCCATCTCAAAAAAAAAAAATTTTTTTTTGTAGTGACAAGGTGTCACTGTGTTGCCAGGGCTGGTCTCAAACTTCTGGGCTCAAGTGATCCTCCCATTTCGGCCTCCCAAAGTGCTAGGATCACAGGCATGAGTCACTGTGCCTGGTCTTCAAGTTGTTATTAAAGCATGTTTACCCACATTATGCACATGGTATAATGGAAAGTATTGTTGTGGAAGTTAGGAGATAGGGATTCTAGCCTAGCTTTTTATTTTTTTGGGACAAGGTCTCACTTTTTCGCCCCAGGCCGAAGTGCAGTTGTGCGATCTCGGCTCACTGCAACCTCCAACTCTCAGGTTCAAGCAATTCTCCCACGTCAGCCTCCCGAGTAGCTGGGATTACAGGCATGCGCCACCACGCCCGGCTAATTTTTGTAGTTTTAGTAGACACAGGGTTTCACCATGTTGGCCAGGCTGGTCTTGAACTCCCGACCTCAGGTGATCCACCCACCTTGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACCGCACCCGGCCTCTAGCGTAACTTTTACATCCTGAACTGACCTTAAGAAAGTATAACTTTAGGCCTGTTTCATCTGTAAAATGTTAATGTCATAGGAGATGATCTTTTGAGATTTCTTTCAGCTCTGATAATTTTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGAGATGGAGTCTTGCTCTGTCGCCCGGGCTGGAGTGCAGTGGTACCATCTCGGCTCACTGCAAGCTCCACCTCCTGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTACAGGCGCCTGCCACCACGCCTGGCTAATTTTTTGTATTTTTAGTAGAGACGAGGTTTCACCGTGTTAGCCAGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCAGCCTCCCAAAGTGCTGGGATTACAGGTCTGAGCCGCCGCGCCCGGCCTAGAATATTTGTTTCGATTATTCTAAATCTGGTGACATTTCTTTTGTTTTTAAGTTAAATCTTCAGTAAAAAGAATAAATGCCACCTAGAGGACAGAAAAATTTTTACAGTAGATTATCACAGACCTCATGACTCATTACTTTGGTGTATAAAATGGCCTTTGTATGGTGTCAGCACCTGGGAATGTCTCAAGGGGTGTTCATTGACCTTCTGGACTATCTGGAAATATTTTGATATTTATTGGCTGGGCGCGGTGGCTCATGCCTGTAATTCCAGCACCTCGGGAGGCCAAGTTAGGTGGATCACTTGAGGTCAGGAGTTTGAGATCAGCCTGGCCAACTAAGTTAGTTGACTATTTGTGAAATTTCCCTCTCCAAATAGGAAAGATAGGATTGGAAACATTATTCAGAAGGAAGAAGTTTTAAAGAAGGGCAGGCTTAAAGACTATCTAATGAATTTACCAATATGGTAAAACCCCATCTTTACTAAAAATACAAAAATTAGCCAGGCGTGGTGGTGGGCGCCTGTAATCCCAGCTACCTGGGATGTTGAGGGATGAGAATCACTTGAACCCAGGAGGCAAAAGTCACAGTGAGCCGAGATTGCACCACTGCACTCCAGACTGGGCTATAGAGCAAAACTCTGTCTCAAAAAAAAAAAGGAAAAAAAAAAAAGAAATTTTGATATTTATGTGAGAATGACTTTTCACGGTGTTCTTAATAGCGCAAGTTTTGTTTAGGAGAGCACATTCCAACTTACTTGCTTCTATAAATATACCGTGTAATCTAGGGCTTAAAGAATATGTACAATGTCTTTTTCTCTCCCCTAGTCTTCCCCTTTTCTCACTAGTTATATCCTTGACTGAAGAGCTATTTCATTCTCAAGTCTTAGGAATGCAGGGTGAAGCAAAACAGATGAATTTTTAAAGCACTTAACCAGGCTGTATGAAATCACAGTCTGTTGTCTAAAATTGTAAGGGACGGTTAGTAGTACTCTCCCCTTTCTCAAACCAAATCTTTGGTTGTTTTAAGGAAGGGAAATTAAATTCCTGTGTGCTAGATTTTCAACATAAAATTTAAAAAACTGGAATAATGTTGCATTTTATGTGTATAACAGTATAATGCTTTGTTTTAGGTGGGAGAAGGAGAGAAATTGGTGAGGGCTCTTTTTGCTGTGGCTCGAGAACTTCAACCTTCTATAATTTTTATAGGTAAGAACATATTTTCCAACTAAGTTATTGACTATTTGTGAAATTTCCCTCTCCAAATAGGAAAGATACGATTGGAAACATTATTCAGAAGGAAGAAGTTTTAAAGAAGGGCAAGCTTAAAGACTATCTAATGAATTTAGTAGGACCCACTATATTAATAAGTAGTAAACTAGATTAATCTCAGATGACTCACATAGCTTGGTCTTTAATTAAAGTCTTATACTTGTATTTCCTCTAGATGAAGTTGATAGCCTTTTGTGTGAAAGAAGAGAAGGGGAGCACGATGCTAGTAGACGCCTAAAAACTGAATTTCTAATAGAATTTGATGGTGTAAGTGTTGATTATGATATTTTTAATGTGGCAGCATTTTAGTATATTTTCCTATTAAATGGCCAAGGTTAAAAATACAAATATCTTTATATTTGTTATTACTTTTCTAAATGAATTGAAAAAAGATTTTTTGCTTGTAGGTACAGTCTGCTGGAGATGACAGAGTACTTGTAATGGGTGCAACTAATAGGCCACAAGAGCTTGATGAGGCTGTTCTCAGGTAGGGAGATTTATATGGAAATACATGCATTTATTACAGACAATATTTACTCATGTGTCCATCTTACATATTATTTCCTTACTCTCAGTTTTAAGACTAAATTCACTATTTTCTTCCAGTACTATCTCTAGCCTCTTGTTACCAACTACATAAGGATTTTGAGGTCAACAGCTTGATATCAGGAGAATTAGTCTAGTAAAGGTTTAGTTACGGTTTTAGGCAAATTGGTCAGTTCTTCTGGGTTGCATTAAATTATCTTTAAACTTGAAAATTGATTCTTACCGTCTTTTATTGGGCTTCATGAGAAAATAATCAAATCAGGGTTCATGGAAAATGTGTTTTCTGTTCTTGTGTGTTTGAGCAGTTTATTCCCTTCATACTGGAAGGACGGTTTGGGTCAGCATAAAATTCTTGGGCATCCTTTCCCAAGGAATTTACAATATTGCTCCATTGTTTCTAGATTGGCTGTAGTAGTGTAAAAGTCTGAATCCAAATTGATTTTTTCAAATTTGTAAAATAACTT"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "spastin"}}], "symbols": [{"value": {"type": "Preferred", "value": "SPAST"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 32063556, "stop": 32157637, "display_start": 32063556, "display_stop": 32157637, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 32288679, "stop": 32382705, "display_start": 32288679, "display_stop": 32382705, "strand": "+", "variant_length": 94027, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "6683"}, {"db": "OMIM", "id": "604277", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:11233"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "17895902"}], "type": "general"}], "xrefs": [{"db": "dbVar", "id": "nssv7487215"}, {"db": "dbVar", "id": "nsv1197506"}, {"db": "OMIM", "id": "604277.0022", "type": "Allelic variant"}], "comments": [{"text": "NCBI staff reviewed the sequence information reported in PubMed 17895902 supplementary figure to determine the location of this allele on the current reference sequence.", "type": "public", "datasource": "NCBI curation"}, {"text": "Genomic duplication of exons 10-12 of gene SPAST plus flanking intronic sequences.", "type": "public", "datasource": "NCBI curation"}], "id": 20716}], "names": [{"value": {"type": "Preferred", "value": "NM_014946.4(SPAST):c.1246-2896_1493+523dup"}}], "xrefs": [{"db": "ClinGen", "id": "CA10575495"}], "id": 5677}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Hereditary spastic paraplegia 4"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0008438"}]}, {"value": {"type": "Alternate", "value": "Spastic paraplegia 4, autosomal dominant"}, "xrefs": [{"db": "Genetic Alliance", "id": "Spastic+paraplegia+4/6695"}]}, {"value": {"type": "Alternate", "value": "Familial spastic paraplegia autosomal dominant 2"}}], "symbols": [{"value": {"type": "Alternate", "value": "FSP2"}, "xrefs": [{"db": "OMIM", "id": "182601", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "SPG4"}, "xrefs": [{"db": "OMIM", "id": "182601", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "Spastic paraplegia 4 (SPG4; also known as SPAST-HSP) is characterized by insidiously progressive bilateral lower-limb gait spasticity. More than 50% of affected individuals have some weakness in the legs and impaired vibration sense at the ankles. Sphincter disturbances are very common. Onset is insidious, mostly in young adulthood, although symptoms may start as early as age one year and as late as age 76 years. Intrafamilial variation is considerable."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1160"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "4925"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301339"}, {"source": "BookShelf", "value": "NBK1160"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0008438"}, {"db": "MedGen", "id": "C1866855"}, {"db": "Orphanet", "id": "100985"}, {"db": "OMIM", "id": "182601", "type": "MIM"}]}], "id": 6399}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 63534}, "record_status": "current", "title": "NM_014946.4(SPAST):c.1246-2896_1493+523dup AND Hereditary spastic paraplegia 4", "clinvar_assertions": [{"id": 26213, "submission_id": {"local_key": "604277.0022_SPASTIC PARAPLEGIA 4", "submitter": "OMIM", "title": "SPAST, EX10-12DUP_SPASTIC PARAPLEGIA 4", "submitter_date": "2019-10-09"}, "clinvar_accession": {"acc": "SCV000026213", "version": 4, "type": "SCV", "date_updated": "2020-01-16", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2007-12-01"}], "external_ids": [{"db": "OMIM", "id": "604277.0022", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In affected individuals of a large Brazilian kindred with spastic paraplegia-4 (SPG4; 182601), originally reported by Starling et al. (2002), Mitne-Neto et al. (2007) identified a heterozygous tandem duplication of exons 10 through 12 of the SPAST gene. Long-range PCR and sequencing showed nonhomology of the sequences contributing to the novel fusion. The duplication was predicted to result in premature termination and disruption of enzymatic activity. Twelve of 30 mutation carriers had no clinical complaints. Among these patients, 9 of 14 female carriers had no complaints, indicating sex-dependent penetrance in this family, with women being partially protected."}, "citations": [{"ids": [{"source": "PubMed", "value": "12471215"}]}, {"ids": [{"source": "PubMed", "value": "17895902"}]}], "xrefs": [{"db": "OMIM", "id": "182601", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "SPAST, EX10-12DUP"}}], "attributes": [{"type": "NonHGVS", "value": "EX10-12DUP"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "SPAST"}}]}], "xrefs": [{"db": "OMIM", "id": "604277.0022", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "SPASTIC PARAPLEGIA 4"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000006776", "version": 2, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2008-03-15"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a 5-year-old boy with spondylocarpotarsal synostosis syndrome (SCT; 272460), Mitter et al. (2008) detected a homozygous 6010C-T transition in exon 36 of the FLNB gene, resulting in an arg2004-to-ter (R2004X) substitution. In addition to the typical findings of SCT, the boy demonstrated ossification delay of multiple epiphyses and bilateral proximal femoral epiphyseal dysplasia."}, "citations": [{"ids": [{"source": "PubMed", "value": "18257094"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000006407", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_001457.4(FLNB):c.6010C>T (p.Arg2004Ter)"}}], "canonical_spdi": "NC_000003.12:58148770:C:T", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001164319.2:c.5938C>T"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001164318.2:c.5977C>T"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001457.4:c.6010C>T"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001164317.2:c.6103C>T"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_012801.1:g.145372C>T"}, {"type": "HGVS, genomic, top level", "value": "NC_000003.12:g.58148771C>T", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000003.11:g.58134498C>T", "integer_value": 37}, {"type": "HGVS, protein, RefSeq", "value": "NP_001157791.1:p.Arg1980Ter"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001157790.1:p.Arg1993Ter"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001448.2:p.Arg2004Ter"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001157789.1:p.Arg2035Ter"}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_001164317.2:c.6103C>T"}]}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_001164318.2:c.5977C>T"}]}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_001164319.2:c.5938C>T"}]}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_001457.4:c.6010C>T"}]}, {"type": "ProteinChange1LetterCode", "value": "R1980*"}, {"type": "ProteinChange1LetterCode", "value": "R1993*"}, {"type": "ProteinChange1LetterCode", "value": "R2004*"}, {"type": "ProteinChange1LetterCode", "value": "R2035*"}, {"type": "ProteinChange3LetterCode", "value": "ARG2004TER"}], "cytogenic_locations": ["3p14.3"], "sequence_locations": [{"assembly": "GRCh38", "chr": "3", "accession": "NC_000003.12", "start": 58148771, "stop": 58148771, "display_start": 58148771, "display_stop": 58148771, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 58148771, "reference_allele_vcf": "C", "alternate_allele_vcf": "T"}, {"assembly": "GRCh37", "chr": "3", "accession": "NC_000003.11", "start": 58134498, "stop": 58134498, "display_start": 58134498, "display_stop": 58134498, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 58134498, "reference_allele_vcf": "C", "alternate_allele_vcf": "T"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "filamin B"}}], "symbols": [{"value": {"type": "Preferred", "value": "FLNB"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "3", "accession": "NC_000003.12", "start": 58008422, "stop": 58172251, "display_start": 58008422, "display_stop": 58172251, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "3", "accession": "NC_000003.11", "start": 57994126, "stop": 58157981, "display_start": 57994126, "display_stop": 58157981, "strand": "+", "variant_length": 163856, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "2317"}, {"db": "OMIM", "id": "603381", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:3755"}]}], "xrefs": [{"db": "OMIM", "id": "603381.0013", "type": "Allelic variant"}, {"db": "dbSNP", "id": "121908897", "type": "rs"}], "id": 21446}], "names": [{"value": {"type": "Preferred", "value": "NM_001457.4(FLNB):c.6010C>T (p.Arg2004Ter)"}}], "xrefs": [{"db": "ClinGen", "id": "CA253861"}], "id": 6407}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Spondylocarpotarsal synostosis syndrome"}, "xrefs": [{"db": "Genetic Alliance", "id": "Spondylocarpotarsal+synostosis+syndrome/6801"}, {"db": "MONDO", "id": "MONDO:0010094"}]}, {"value": {"type": "Alternate", "value": "Spondylocarpotarsal syndrome"}}, {"value": {"type": "Alternate", "value": "Synspondylism congenital"}}, {"value": {"type": "Alternate", "value": "Vertebral fusion with carpal coalition"}}, {"value": {"type": "Alternate", "value": "Scoliosis, congenital with unilateral unsegmented bar"}}], "symbols": [{"value": {"type": "Preferred", "value": "SCT"}, "xrefs": [{"db": "OMIM", "id": "272460", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic."}, "xrefs": [{"db": "GeneReviews", "id": "NBK2534"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301736"}, {"source": "BookShelf", "value": "NBK2534"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0010094"}, {"db": "MedGen", "id": "C1848934"}, {"db": "Orphanet", "id": "3275"}, {"db": "OMIM", "id": "272460", "type": "MIM"}]}], "id": 1773}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 64279}, "record_status": "current", "title": "NM_001457.4(FLNB):c.6010C>T (p.Arg2004Ter) AND Spondylocarpotarsal synostosis syndrome", "clinvar_assertions": [{"id": 26972, "submission_id": {"local_key": "603381.0013_SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME", "submitter": "OMIM", "title": "FLNB, ARG2004TER_SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME", "submitter_date": "2011-08-22"}, "clinvar_accession": {"acc": "SCV000026972", "version": 1, "type": "SCV", "date_updated": "2013-04-04", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2008-03-15"}], "external_ids": [{"db": "OMIM", "id": "603381.0013", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a 5-year-old boy with spondylocarpotarsal synostosis syndrome (SCT; 272460), Mitter et al. (2008) detected a homozygous 6010C-T transition in exon 36 of the FLNB gene, resulting in an arg2004-to-ter (R2004X) substitution. In addition to the typical findings of SCT, the boy demonstrated ossification delay of multiple epiphyses and bilateral proximal femoral epiphyseal dysplasia."}, "citations": [{"ids": [{"source": "PubMed", "value": "18257094"}]}], "xrefs": [{"db": "OMIM", "id": "272460", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "FLNB, ARG2004TER"}}], "attributes": [{"type": "NonHGVS", "value": "ARG2004TER"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "FLNB"}}]}], "xrefs": [{"db": "OMIM", "id": "603381.0013", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000006777", "version": 3, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2008-05-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In an Italian girl with spondylocarpotarsal synostosis syndrome (SCT; 272460), born of consanguineous parents, Brunetti-Pierri et al. (2008) identified a homozygous 5548G-T transversion in the FLNB gene, resulting in a gly1850-to-ter (G1850X) substitution. She had short stature, scoliosis, short trunk, delayed bone age, vertebral fusions, and capitate-hamate fusion. She did not have facial dysmorphic features. Growth hormone (GH) deficiency was documented, but there was no response to GH administration. MRI scan did not show any abnormality of the hypothalamo-pituitary area, but there was platybasia and basilar impression, stenosis of the foramen magnum, but no signs of medullary compression at the cervicomedullary junction. A younger brother, who was heterozygous for the mutation, had short stature and transient GH deficiency."}, "citations": [{"ids": [{"source": "PubMed", "value": "18386804"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000006408", "version": 2, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_001457.4(FLNB):c.5548G>T (p.Gly1850Ter)"}}], "canonical_spdi": "NC_000003.12:58146042:G:T", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001164319.2:c.5476G>T"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001164318.2:c.5515G>T"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001457.4:c.5548G>T"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001164317.2:c.5641G>T"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_012801.1:g.142644G>T"}, {"type": "HGVS, genomic, top level", "value": "NC_000003.12:g.58146043G>T", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000003.11:g.58131770G>T", "integer_value": 37}, {"type": "HGVS, protein, RefSeq", "value": "NP_001157791.1:p.Gly1826Ter"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001157790.1:p.Gly1839Ter"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001448.2:p.Gly1850Ter"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001157789.1:p.Gly1881Ter"}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_001164317.2:c.5641G>T"}]}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_001164318.2:c.5515G>T"}]}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_001164319.2:c.5476G>T"}]}, {"type": "MolecularConsequence", "value": "nonsense", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001587"}, {"db": "RefSeq", "id": "NM_001457.4:c.5548G>T"}]}, {"type": "ProteinChange1LetterCode", "value": "G1826*"}, {"type": "ProteinChange1LetterCode", "value": "G1839*"}, {"type": "ProteinChange1LetterCode", "value": "G1850*"}, {"type": "ProteinChange1LetterCode", "value": "G1881*"}, {"type": "ProteinChange3LetterCode", "value": "GLY1850TER"}], "cytogenic_locations": ["3p14.3"], "sequence_locations": [{"assembly": "GRCh38", "chr": "3", "accession": "NC_000003.12", "start": 58146043, "stop": 58146043, "display_start": 58146043, "display_stop": 58146043, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 58146043, "reference_allele_vcf": "G", "alternate_allele_vcf": "T"}, {"assembly": "GRCh37", "chr": "3", "accession": "NC_000003.11", "start": 58131770, "stop": 58131770, "display_start": 58131770, "display_stop": 58131770, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 58131770, "reference_allele_vcf": "G", "alternate_allele_vcf": "T"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "filamin B"}}], "symbols": [{"value": {"type": "Preferred", "value": "FLNB"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "3", "accession": "NC_000003.12", "start": 58008422, "stop": 58172251, "display_start": 58008422, "display_stop": 58172251, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "3", "accession": "NC_000003.11", "start": 57994126, "stop": 58157981, "display_start": 57994126, "display_stop": 58157981, "strand": "+", "variant_length": 163856, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "2317"}, {"db": "OMIM", "id": "603381", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:3755"}]}], "xrefs": [{"db": "OMIM", "id": "603381.0014", "type": "Allelic variant"}, {"db": "dbSNP", "id": "121908898", "type": "rs"}], "id": 21447}], "names": [{"value": {"type": "Preferred", "value": "NM_001457.4(FLNB):c.5548G>T (p.Gly1850Ter)"}}], "xrefs": [{"db": "ClinGen", "id": "CA253863"}], "id": 6408}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Spondylocarpotarsal synostosis syndrome"}, "xrefs": [{"db": "Genetic Alliance", "id": "Spondylocarpotarsal+synostosis+syndrome/6801"}, {"db": "MONDO", "id": "MONDO:0010094"}]}, {"value": {"type": "Alternate", "value": "Spondylocarpotarsal syndrome"}}, {"value": {"type": "Alternate", "value": "Synspondylism congenital"}}, {"value": {"type": "Alternate", "value": "Vertebral fusion with carpal coalition"}}, {"value": {"type": "Alternate", "value": "Scoliosis, congenital with unilateral unsegmented bar"}}], "symbols": [{"value": {"type": "Preferred", "value": "SCT"}, "xrefs": [{"db": "OMIM", "id": "272460", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic."}, "xrefs": [{"db": "GeneReviews", "id": "NBK2534"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301736"}, {"source": "BookShelf", "value": "NBK2534"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0010094"}, {"db": "MedGen", "id": "C1848934"}, {"db": "Orphanet", "id": "3275"}, {"db": "OMIM", "id": "272460", "type": "MIM"}]}], "id": 1773}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 64280}, "record_status": "current", "title": "NM_001457.4(FLNB):c.5548G>T (p.Gly1850Ter) AND Spondylocarpotarsal synostosis syndrome", "clinvar_assertions": [{"id": 26973, "submission_id": {"local_key": "603381.0014_SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME", "submitter": "OMIM", "title": "FLNB, GLY1850TER_SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME", "submitter_date": "2019-06-05"}, "clinvar_accession": {"acc": "SCV000026973", "version": 2, "type": "SCV", "date_updated": "2019-06-09", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2008-05-01"}], "external_ids": [{"db": "OMIM", "id": "603381.0014", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In an Italian girl with spondylocarpotarsal synostosis syndrome (SCT; 272460), born of consanguineous parents, Brunetti-Pierri et al. (2008) identified a homozygous 5548G-T transversion in the FLNB gene, resulting in a gly1850-to-ter (G1850X) substitution. She had short stature, scoliosis, short trunk, delayed bone age, vertebral fusions, and capitate-hamate fusion. She did not have facial dysmorphic features. Growth hormone (GH) deficiency was documented, but there was no response to GH administration. MRI scan did not show any abnormality of the hypothalamo-pituitary area, but there was platybasia and basilar impression, stenosis of the foramen magnum, but no signs of medullary compression at the cervicomedullary junction. A younger brother, who was heterozygous for the mutation, had short stature and transient GH deficiency."}, "citations": [{"ids": [{"source": "PubMed", "value": "18386804"}]}], "xrefs": [{"db": "OMIM", "id": "272460", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "FLNB, GLY1850TER"}}], "attributes": [{"type": "NonHGVS", "value": "GLY1850TER"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "FLNB"}}]}], "xrefs": [{"db": "OMIM", "id": "603381.0014", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000008451", "version": 3, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "1997-07-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a mother and son with ulnar-mammary syndrome (UMS; 181450), Bamshad et al. (1997) found that the TBX3 gene had deletion of nucleotide 227, a thymidine, resulting in shift of the reading frame and a premature termination codon after 11 novel amino acids. A hand x-ray in the mother showed complete absence of the fourth digit (metacarpal and phalanges) and fusion of the capitate and hamate bones on the right. The mutated protein in this family was predicted to encode a markedly truncated protein containing only 86 amino acids and lacking the entire T-box domain. This mutant protein should be incapable of binding DNA. Affected members of this family demonstrated limb and apocrine anomalies."}, "citations": [{"ids": [{"source": "PubMed", "value": "9207801"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000007987", "version": 1, "measures": [{"type": "deletion", "names": [{"value": {"type": "Preferred", "value": "NM_005996.4(TBX3):c.227del (p.Ile76fs)"}}], "canonical_spdi": "NC_000012.12:114682973:A:", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_005996.4:c.227del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_016569.4:c.227del"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_008315.1:g.6191del"}, {"type": "HGVS, genomic, top level", "value": "NC_000012.12:g.114682974del", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000012.11:g.115120779del", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_005996.3:c.227delT"}, {"type": "HGVS, protein, RefSeq", "value": "NP_005987.3:p.Ile76fs"}, {"type": "HGVS, protein, RefSeq", "value": "NP_057653.3:p.Ile76fs"}, {"type": "MolecularConsequence", "value": "frameshift variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001589"}, {"db": "RefSeq", "id": "NM_005996.4:c.227del"}]}, {"type": "MolecularConsequence", "value": "frameshift variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001589"}, {"db": "RefSeq", "id": "NM_016569.4:c.227del"}]}, {"type": "ProteinChange1LetterCode", "value": "I76fs"}], "cytogenic_locations": ["12q24.21"], "sequence_locations": [{"assembly": "GRCh38", "chr": "12", "accession": "NC_000012.12", "start": 114682974, "stop": 114682974, "display_start": 114682974, "display_stop": 114682974, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 114682973, "reference_allele_vcf": "GA", "alternate_allele_vcf": "G"}, {"assembly": "GRCh37", "chr": "12", "accession": "NC_000012.11", "start": 115120779, "stop": 115120779, "display_start": 115120779, "display_stop": 115120779, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 115120778, "reference_allele_vcf": "GA", "alternate_allele_vcf": "G"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "T-box transcription factor 3"}}], "symbols": [{"value": {"type": "Preferred", "value": "TBX3"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "12", "accession": "NC_000012.12", "start": 114670255, "stop": 114684175, "display_start": 114670255, "display_stop": 114684175, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "12", "accession": "NC_000012.11", "start": 115108058, "stop": 115121968, "display_start": 115108058, "display_stop": 115121968, "strand": "-", "variant_length": 13911, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "6926"}, {"db": "OMIM", "id": "601621", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:11602"}]}], "xrefs": [{"db": "OMIM", "id": "601621.0001", "type": "Allelic variant"}, {"db": "dbSNP", "id": "1592851924", "type": "rs"}], "comments": [{"text": "ClinGen staff contributed the HGVS expression for this variant.", "type": "public", "datasource": "ClinGen"}], "id": 23026}], "names": [{"value": {"type": "Preferred", "value": "NM_005996.4(TBX3):c.227del (p.Ile76fs)"}}], "id": 7987}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Ulnar-mammary syndrome"}, "xrefs": [{"db": "Genetic Alliance", "id": "Ulnar-mammary+syndrome/7292"}, {"db": "MONDO", "id": "MONDO:0008411"}]}, {"value": {"type": "Alternate", "value": "Schinzel syndrome"}}, {"value": {"type": "Alternate", "value": "Ulnar-mammary syndrome of Pallister"}}, {"value": {"type": "Alternate", "value": "PALLISTER ULNAR-MAMMARY SYNDROME"}, "xrefs": [{"db": "OMIM", "id": "181450", "type": "MIM"}]}], "symbols": [{"value": {"type": "Preferred", "value": "UMS"}, "xrefs": [{"db": "OMIM", "id": "181450", "type": "MIM"}]}], "attributes": [{"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "118"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0008411"}, {"db": "MedGen", "id": "C1866994"}, {"db": "Orphanet", "id": "3138"}, {"db": "OMIM", "id": "181450", "type": "MIM"}]}], "id": 2173}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 65954}, "record_status": "current", "title": "NM_005996.4(TBX3):c.227del (p.Ile76fs) AND Ulnar-mammary syndrome", "clinvar_assertions": [{"id": 28659, "submission_id": {"local_key": "601621.0001_ULNAR-MAMMARY SYNDROME", "submitter": "OMIM", "title": "TBX3, 1-BP DEL, 227T_ULNAR-MAMMARY SYNDROME", "submitter_date": "2017-04-18"}, "clinvar_accession": {"acc": "SCV000028659", "version": 2, "type": "SCV", "date_updated": "2015-10-11", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "1997-07-01"}], "external_ids": [{"db": "OMIM", "id": "601621.0001", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a mother and son with ulnar-mammary syndrome (UMS; 181450), Bamshad et al. 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Affected members of this family demonstrated limb and apocrine anomalies."}, "citations": [{"ids": [{"source": "PubMed", "value": "9207801"}]}], "xrefs": [{"db": "OMIM", "id": "181450", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "TBX3, 1-BP DEL, 227T"}}], "attributes": [{"type": "NonHGVS", "value": "1-BP DEL, 227T"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "TBX3"}}]}], "xrefs": [{"db": "OMIM", "id": "601621.0001", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "ULNAR-MAMMARY SYNDROME"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000008458", "version": 3, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "1999-03-16"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a family with Holt-Oram syndrome (HOS; 142900), Basson et al. (1999) identified a gly80-to-arg substitution in the TBX5 gene. They found that this mutation caused significant cardiac malformations but only minor skeletal abnormalities."}, "citations": [{"ids": [{"source": "PubMed", "value": "10077612"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000007994", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_181486.4(TBX5):c.238G>A (p.Gly80Arg)"}}], "canonical_spdi": "NC_000012.12:114401829:C:T", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_670t1:c.238G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000192.3:c.238G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_181486.4:c.238G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_080717.4:c.88G>A"}, {"type": "HGVS, genomic, LRG", "value": "LRG_670:g.11613G>A"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_007373.1:g.11613G>A"}, {"type": "HGVS, genomic, top level", "value": "NC_000012.12:g.114401830C>T", "integer_value": 38}, {"type": "HGVS, 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"value": "G30R"}, {"type": "ProteinChange1LetterCode", "value": "G80R"}, {"type": "ProteinChange3LetterCode", "value": "GLY80ARG"}], "cytogenic_locations": ["12q24.21"], "sequence_locations": [{"assembly": "GRCh38", "chr": "12", "accession": "NC_000012.12", "start": 114401830, "stop": 114401830, "display_start": 114401830, "display_stop": 114401830, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 114401830, "reference_allele_vcf": "C", "alternate_allele_vcf": "T"}, {"assembly": "GRCh37", "chr": "12", "accession": "NC_000012.11", "start": 114839635, "stop": 114839635, "display_start": 114839635, "display_stop": 114839635, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 114839635, "reference_allele_vcf": "C", "alternate_allele_vcf": "T"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "T-box 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"Preferred", "value": "NM_181486.4(TBX5):c.238G>A (p.Gly80Arg)"}}], "xrefs": [{"db": "ClinGen", "id": "CA254300"}], "id": 7994}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Holt-Oram syndrome"}, "xrefs": [{"db": "Genetic Alliance", "id": "Holt-Oram+syndrome/3457"}, {"db": "MONDO", "id": "MONDO:0007732"}, {"db": "SNOMED CT", "id": "19092004"}]}, {"value": {"type": "Alternate", "value": "Ventriculo-radial syndrome"}}, {"value": {"type": "Alternate", "value": "Atrio digital syndrome"}}, {"value": {"type": "Alternate", "value": "Cardiac-limb syndrome"}}, {"value": {"type": "Alternate", "value": "Heart-hand syndrome, type 1"}}, {"value": {"type": "Alternate", "value": "HOS 1"}}, {"value": {"type": "Alternate", "value": "TBX5-Related Holt-Oram Syndrome"}}], "symbols": [{"value": {"type": "Preferred", "value": "HOS"}, "xrefs": [{"db": "OMIM", "id": "142900", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "HOS1"}, 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Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, sloping shoulders, and restriction of shoulder joint movement. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease. While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1111"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301290"}, {"source": "BookShelf", "value": "NBK1111"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0007732"}, {"db": "MedGen", "id": "C0265264"}, {"db": "Orphanet", "id": "392"}, {"db": "OMIM", "id": "142900", "type": "MIM"}]}], "id": 2174}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 65961}, "record_status": "current", "title": "NM_181486.4(TBX5):c.238G>A (p.Gly80Arg) AND Holt-Oram syndrome", "clinvar_assertions": [{"id": 28666, "submission_id": {"local_key": "601620.0004_HOLT-ORAM SYNDROME", "submitter": "OMIM", "title": "TBX5, GLY80ARG_HOLT-ORAM SYNDROME", "submitter_date": "2016-09-28"}, "clinvar_accession": {"acc": "SCV000028666", "version": 2, "type": "SCV", "date_updated": "2016-10-02", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "1999-03-16"}], "external_ids": [{"db": "OMIM", "id": "601620.0004", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a family with Holt-Oram syndrome (HOS; 142900), Basson et al. (1999) identified a gly80-to-arg substitution in the TBX5 gene. They found that this mutation caused significant cardiac malformations but only minor skeletal abnormalities."}, "citations": [{"ids": [{"source": "PubMed", "value": "10077612"}]}], "xrefs": [{"db": "OMIM", "id": "142900", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "TBX5, GLY80ARG"}}], "attributes": [{"type": "NonHGVS", "value": "GLY80ARG"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "TBX5"}}]}], "xrefs": [{"db": "OMIM", "id": "601620.0004", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "HOLT-ORAM SYNDROME"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000008460", "version": 4, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2000-06-05"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a Chinese family with Holt-Oram syndrome (HOS; 142900), Yang et al. 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"Preferred", "value": "Pendular nystagmus"}}], "xrefs": [{"db": "HP", "id": "HP:0012043"}]}]}}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_020366.3:c.900_906+14delTCAAGAGGTGAGTTGCCATCA"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "RPGRIP1"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "OMIM", "id": "613826", "type": "MIM"}]}]}, "study_description": "Identfication of novel variants using exome sequencing in Mendelian Disorders.", "comments": [{"text": "Indel variant"}]}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000256480", "version": 2, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2016-10-23"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "likely pathogenic", "date_last_evaluated": "2014-01-01"}, "assertion": 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"NC_000021.9:g.46125855dup", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000021.8:g.47545769dup", "integer_value": 37}, {"type": "HGVS, protein"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001840.3:p.Ile681fs"}, {"type": "HGVS, protein, RefSeq", "value": "NP_478054.2:p.Ile681fs"}, {"type": "HGVS, protein, RefSeq", "value": "NP_478055.2:p.Ile681fs"}, {"type": "MolecularConsequence", "value": "frameshift variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001589"}, {"db": "RefSeq", "id": "NM_001849.4:c.2040dup"}]}, {"type": "MolecularConsequence", "value": "frameshift variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001589"}, {"db": "RefSeq", "id": "NM_058174.3:c.2040dup"}]}, {"type": "MolecularConsequence", "value": "frameshift variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001589"}, {"db": "RefSeq", "id": "NM_058175.3:c.2040dup"}]}, {"type": "ProteinChange1LetterCode", "value": "I681fs"}], "cytogenic_locations": ["21q22.3"], "sequence_locations": [{"assembly": "GRCh38", "chr": "21", "accession": "NC_000021.9", "start": 46125854, "stop": 46125855, "display_start": 46125854, "display_stop": 46125855, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 46125854, "reference_allele_vcf": "G", "alternate_allele_vcf": "GT"}, {"assembly": "GRCh37", "chr": "21", "accession": "NC_000021.8", "start": 47545768, "stop": 47545769, "display_start": 47545768, "display_stop": 47545769, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 47545768, "reference_allele_vcf": "G", "alternate_allele_vcf": "GT"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "collagen type VI alpha 2 chain"}}], "symbols": [{"value": {"type": "Preferred", "value": "COL6A2"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "21", "accession": "NC_000021.9", "start": 46098112, "stop": 46132848, "display_start": 46098112, "display_stop": 46132848, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "21", "accession": "NC_000021.8", "start": 47518032, "stop": 47552762, "display_start": 47518032, "display_stop": 47552762, "strand": "+", "variant_length": 34731, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "1292"}, {"db": "OMIM", "id": "120240", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:2212"}]}], "xrefs": [{"db": "dbSNP", "id": "886039905", "type": "rs"}], "id": 260941}], "names": [{"value": {"type": "Preferred", "value": "NM_001849.4(COL6A2):c.2040dup (p.Ile681fs)"}}], "xrefs": [{"db": "ClinGen", "id": "CA10588991"}], "id": 266110}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Ullrich congenital muscular dystrophy 1"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0009681"}]}, {"value": {"type": "Alternate", "value": "Late onset scleroatonic familial myopathy (subtype)"}}, {"value": {"type": "Alternate", "value": "ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1, AUTOSOMAL RECESSIVE"}, "xrefs": [{"db": "OMIM", "id": "120220.0009", "type": "Allelic variant"}, {"db": "OMIM", "id": "120220.0010", "type": "Allelic variant"}, {"db": "OMIM", "id": "120220.0011", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0002", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0003", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0004", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0006", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0007", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0012", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0015", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0016", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0020", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0021", "type": "Allelic variant"}, {"db": "OMIM", "id": "120250.0002", "type": "Allelic variant"}, {"db": "OMIM", "id": "120250.0003", "type": "Allelic variant"}]}, {"value": {"type": "Alternate", "value": "ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1, DIGENIC, COL6A1/COL6A2"}, "xrefs": [{"db": "OMIM", "id": "120220.0014", "type": "Allelic variant"}, {"db": "OMIM", "id": "120240.0014", "type": "Allelic variant"}]}], "symbols": [{"value": {"type": "Preferred", "value": "UCMD1"}, "xrefs": [{"db": "OMIM", "id": "254090", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "UCMD"}}], "attributes": [{"value": {"type": "public definition", "value": "Collagen VI-related dystrophies (COL6-RDs) represent a continuum of overlapping clinical phenotypes with Bethlem muscular dystrophy at the milder end, Ullrich congenital muscular dystrophy (UCMD) at the more severe end, and a phenotype in between UCMD and Bethlem muscular dystrophy, referred to as intermediate COL6-RD. Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures. Hypotonia and delayed motor milestones occur in early childhood; mild hypotonia and weakness may be present congenitally. By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors. The progression of weakness is slow, and more than two thirds of affected individuals older than age 50 years remain independently ambulatory indoors, while relying on supportive means for mobility outdoors. Respiratory involvement is not a consistent feature. UCMD is characterized by congenital weakness, hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints. Decreased fetal movements are frequently reported. Some affected children acquire the ability to walk independently; however, progression of the disease results in a loss of ambulation by age ten to eleven years. Early and severe respiratory insufficiency occurs in all individuals, resulting in the need for nocturnal noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) by age 11 years. Intermediate COL6-RD is characterized by independent ambulation past age 11 years and respiratory insufficiency that is later in onset than in UCMD and results in the need for NIV in the form of BiPAP by the late teens to early 20s. In contrast to individuals with Bethlem muscular dystrophy, those with intermediate COL6-RD typically do not achieve the ability to run, jump, or climb stairs without use of a railing."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1503"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301676"}, {"source": "BookShelf", "value": "NBK1503"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "PubMed", "value": "21078917"}], "type": "practice guideline", "abbrev": "Int'l SCC for CMD, 2010"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0009681"}, {"db": "MedGen", "id": "C0410179"}, {"db": "Orphanet", "id": "75840"}, {"db": "OMIM", "id": "254090", "type": "MIM"}]}], "id": 6476}, "date_created": "2016-10-23", "date_last_updated": "2022-04-23", "id": 620031}, "record_status": "current", "title": "NM_001849.4(COL6A2):c.2040dup (p.Ile681fs) AND Ullrich congenital muscular dystrophy 1", "clinvar_assertions": [{"id": 619944, "submission_id": {"local_key": "chr21:47545768insT", "submitter": "Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS", "submitted_assembly": "GRCh37", "submitter_date": "2016-06-27"}, "clinvar_accession": {"acc": "SCV000323245", "version": 1, "type": "SCV", "date_updated": "2016-10-23", "date_created": "2016-10-23", "org_id": "505641", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["likely pathogenic"], "date_last_evaluated": "2014-01-01"}], "observed_in": [{"sample": {"origin": "unknown", "geographic_origin": "India", "species": {"value": "human", "taxonomy_id": 9606}, "age": [{"age_unit": "years", "value": 0, "type": "minimum"}, {"age_unit": "years", "value": 9, "type": "maximum"}], "affected_status": "yes", "number_tested": 1, "gender": "female", "proband": "yes"}, "methods": ["research"], "observed_data": [{"attribute": {"type": "Homozygote", "integer_value": 1}}], "traits": {"type": "Finding", "traits": [{"type": "Finding", "names": [{"value": {"type": "Preferred", "value": "Failure to thrive"}}], "xrefs": [{"db": "HP", "id": "HP:0001508"}]}, {"type": "Finding", "names": [{"value": {"type": "Preferred", "value": "Neonatal hypotonia"}}], "xrefs": [{"db": "HP", "id": "HP:0001319"}]}, {"type": "Finding", "names": [{"value": {"type": "Preferred", "value": "Proximal muscle weakness"}}], "xrefs": [{"db": "HP", "id": "HP:0003701"}]}]}}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_001849.3:c.2040dupT"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "COL6A2"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "OMIM", "id": "254090", "type": "MIM"}]}]}, "study_description": "Identfication of novel variants using exome sequencing in Mendelian Disorders.", "comments": [{"text": "Indel variant"}]}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000050247", "version": 1, "type": "RCV", "date_updated": "2022-06-05", "date_created": "2013-09-05"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2013-04-22"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "inherited", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "family_data": {"num_families": 2}}, "methods": ["case-control"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 6}}]}], "measures": {"type": "Variant", "acc": "VCV000056966", "version": 1, "measures": [{"type": "indel", "attributes": [{"type": "HGVS, genomic, RefSeqGene", "value": "NG_021416.1:g.615_8308delinsAGAGATCCA"}, {"type": "HGVS, genomic, top level", "value": "NC_000007.14:g.30959635_30967328delinsAGAGATCCA", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000007.13:g.30999250_31006943delinsAGAGATCCA", "integer_value": 37}], "cytogenic_locations": ["7p14.3"], "sequence_locations": [{"assembly": "GRCh38", "chr": "7", "accession": "NC_000007.14", "start": 30959635, "stop": 30967328, "display_start": 30959635, "display_stop": 30967328, "variant_length": 7694, "alternate_allele": "AGAGATCCA", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 30959635, "reference_allele_vcf": "TTGCCAGTACAATGTTGAAGACAAAGCATGATCAAAGCAATGACTACAAAGAGGTAGAAGTGGTCCTGTCAAAGCAAAAGCAGACCGGTCAAGAGCAAAATTCATGATGAAAACAGTTTTGGGGATGCTTGAGGTATTTTGCAGGTTGACTTTCTGGGGAGCCAAAGAACGATAACATCTGCTTATTGTGAAAATGTTTTGAGATAGCCAAAGCTTTAGCAGAAAAATGCCCAGGAAACCTTCACTAGAGAATCCTTCTCCACCACCACAATACTCCTGTTCATTCTTCTCATCAAACAAGGCCAGTTTTGCGAGAGTTTTGATAGGAAATCATTACACATCCACCTCACAGCCATGATTTGGCTTTTCATGATGTCTTTTTGTTTTCTAATCTTAAAAAATCTTTTAAGGGCACTCATTTTTCTTTAGGTAGTAATGTAAAAAAGACTGCATTGACATGGCTAAATTCCCAGGACTCTCAGTGTTTTAGGGATGGATTACATGGTTGGTATCATTGCTTACAAAAGTGTCTTGAAAGCTTATGTTGAGAAATAAAGTTTATATTTTTTATTTTTTAATTCCATATTTCCATGAACTTTGTGAAATCCTCTTGTACAAATAGATTTAGTTCATACCTTTTAACCGCTCAGTAGTATTCCATTGTATGAATAGATCACATTTTGTTTAGCTATTCCTTTCTCATTGGACAATTGTGTTGTTTTCTGGTTTTTACTACATGTTATAAACAACACTGAACTCAGAACGCAAATACCCAGAACTGGAATTTCTGGCTTATAGGGTATGTTCATTCTTAAATTCATTAGATAATATCAAATTGTTTTTCAAAGTGGTTATACAAAATTCACTCTCATCTGCCATTTATGAATGCTCCCATTTCTTTACATTATCTTCCAGACACTGTGTTATCAGACATTAAAGTTTTAGGCAATGTATTAGGTGAAAATGGGTAGCTTATTATTATTTTTATTTTCATATTCTTTAGTATTAGGAATGTTAAACATTTCTTCATCTGTTTATTGGCCTGTATATTTCACTTCTTTTCTGAATTGTCTATTTGTATCATTTGCTCACTTTTCTGAGTTATTTTTATCTTTCTTACTGATTTTTTTCTCTTCTTTCTTTTTTTTTTTGTGACATAGTCTCACTCTGTTGCCCAGGCTGGAGTGCAGTGGCACGATCTTGGCTTACTGCAGACTCCACCTCCCAGGTTCAAGGGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGAACTACAGTTGTGCACCACCAGGCCTGGCTAATTTTTGTATTTTCAGTAGAGACAAGGGTTCACCATATTGGCCAGGCTGACCTGGTGATCCGCCCGCCTTGGCCTCCCAAAGTGCTGGGATTACTGGCGTGAGCCACCACGACCAGCTGATTTTTAGATATTTTTAAAATACATTTTTGATACTACAGATTTGTTTGTCAGGATTGGTTGCAAATATTTCTTTCAGTTTGTAGCAGAAAAATGCTTTTAGTTTTCATCTATGGCATCCTCTCTTGAACATACATTTTAAAATGTTAATGTGGTCACACTTGATTTTTTTCTTTACGATTTTTATTTTATATGACACTCTCCTTTATTCTAAGGCCATAAACATGAATTTCTATTTTTTGAAGCATTTTTATGATTTTGTTGTTTTATAATTAGGATTTTTAACCTAGAATCTATATTTTGTAAATGTGAGCTAGAGATTCAATCTTATTTTTTTGTACAAAGAATCAGCTGTTCCAATCTTACTTGCTGTTAGTCCATCTTTGTTACATGCTGTCATAAATGATTGCCCACTGGATCTAGGCTCTGTATGAGGTTCTTTATAGTACACGGCTTTCCTTGTCCACTTATCCCACCAATCCTATAAGGAAGGTGTTAGTATCATCCCCACTTTTCAGATGGGAAAACGGAGGCTCATATGGTTTGAATGTTTTGTTCTCTCCAAATCTTATGTTGAAATAGACCTGCATTGTTGGAGGTGGGGCCTGGTGGGAGGTGTTTGCGTCATGGGGGTGGGTCCCTCATGAATGGCTTGGTGCCCTCCCCATGGTAATGAGTGAGTTCTCACTCTGCTAGTTCATGCAAGAGTTAGTAGTTTTAAAGAGCCAGCCAGACATCTCCCTTGCTCTCTTGCTCCCTCTCTCACCATGTGATACACCAGGGGTTCCCCCTTCACCTTCCAGCATGAATGGAAGCTTCTTGAGGCCCTCACCAGAAGCAGATGCCAGTGCCATGCTTCCTGTGCAGTCTGCAGAACTGTGAGCCGCAATAAACCTCTTTTTAAAAATATAATACCAAGCCTTGGGTATTCCCTTATAGCAATACAAATGTACTAACACAGAGGTTCAGAAAGGCTAAATGACTTGCCAAATGTATGACAGCTAGCAAGTGATGGAGGCAGAATTTGAATCCTGAGTGTATACAGAATTAGCTAGAGAAGACAGCTCCATGAAGAAACAGGCCTGCAGGGATCCTTGGGGAACATGTACAGTTAGAGCAGGGTTTCTCAGCCTTGGTCTTATTGATCTTTGAGACTGGATAATTCTTCATATGATCAAGGGTGGGGGCATCCTGTGCATTGTAGATGCTTAATAGCATCCCTGGTCTCTACTCATTCGATACCAGGAGCAACTCACCACCCCACTCCTCACCCTAACTCCTAGTTTTTATTTTGATAACAAAAAATGTCTCCAGACATTGCCAAATGTCCCCTAGGGAAGCAAAATTGCTCCAGGTTAGGAACCACTCGTTTAGACAGTAATAACTATTATTAATTATCACTATCAACCTCAATAATTAGCCATCATTAATGCTAATGATATTGATGCTAATTATCAACAGTGATTAATCGTAAGACTTTTTTTTCCTGGTGCTGTTGCTTCTTTGTAGCTGAGGAACAGAAGGTTCTAGCTTTCCCTTCAAGTTATACCTTTTCAGCACTCTGCTTTTCCAACCCGTGAGCTCTCAGCCTGCCAAGAGAGGAGCTCTGCTCTCCCCTAAAAGTGTAAAAGTGTGCAGAGCTCTGTGTGGCATGCTGCTTGCACCCATTTCACAGTTAAGCTCATGAAAACACTTGCACAGGATAGGAGGGTTTTGGAGCTTGGGGTGGTTCATGTTTTTGTTTCGAAATATTTTTTTTTCAGTATTTTGTTGACAATGAAGAAAAATGGAAAAATAAACCCCTGCTGATGTCAAAATAAGCCCTAAATCCAGATGTAGCGGGGGCGAGGAGCCTTCAACATTCATGATGTGATCGGGCTGTAAACATGTCTGGTGTTCTAGCACGCAGCCCAGCAGCTTCTGTGAGTGGAGACGTGCACACAAACATCAGGACCTGTCGGCTACTGGGATATTCAGGTCTTTCAGAGGTGACATCTTTGACATTTCAAAGTGCTGTGCAAGATCCAGGGGCATTTAGAACACTGTCTTTAGCCTGGCCAATGGAGACCCTGCATTTTAAAGTCTAAAACTATAATAAAAGTGACCAGGCAATGAATGTTCAATATAGTTTGCTGTGTAAGTCTTCTCATTTCTGCTACCGATGAGAGTTGTCCTCCCCCTATTCAAGATGGCTTGACCCATGAATCCTTCACAAGGCTTCCAACCAACCTCATTTTCCCCTTTTGCCGTGAGAGTTTTGGAGAGATTTTGATAAGCCCCCATGTGAAATCCAGAGCCTTGATGCTTGCAGCTTCAGCTCACCATCCAGGCCAGCGTCCTTGCCCAGTAAAGGACCCAGGTCTTGCTGAAATGACACATTCCTGGCCAGCCCATGCCAGTGCTTACAGATCATACTTCCTTTCCTAAGACCATTCCAACCCTCCATCTCCACTAATACCATACCCTTCCCCTTCCCCACCAGTTCCACACAGCTCTGACCTCACTCTCCAGCCCTGTGGATGAGGCTAGGAGCACACATCAAATAACCTGGGAGCTTCCCAAGGGCAGGCCCAGGTCCCCTTCCTATTCTTTAAGATCCCATCAATCTGAGGGGTCACTCCAATGATGGCCACCAGAGACCTGGGCTTAGAGAAGAAAGTGGTAGAGAATATTGACCAAGTGACCTGTGGCTGTCACCTCTCTGGGCCCTTGCTATCAGGACAGACACACAAGCAGACTTATAGCCAGAGTAGAAGGCGATGAGGGTGGGGGCTCAGCCCCTGCCTGCTGGAAACAGAGTCCCACCTCAGGGTCAATGCTGAGCTGGGCAGGTGTCCTGCAATCCTGGTGAATATTCAGCGGTCTGTGTCCCCTTGGCTAGCTCCTGCCTATGCAAACAGCCACCTGAGAAGGGGAAGCAGAGGGTGCGGTGGAAACGGCTGTGTCAGGGGACAGCAGGGGAAGGAAGATAGCCAAGGCTTACTGAGGCTGGTGGAGGGAGCCACTGCTGGGCTCACCATGGACCGCCGGATGTGGGGGGCCCACGTCTTCTGCGTGTTGAGCCCGTTACCGACCGTGAGTAGCCAGCTGAGACCCTCTGGCCTCTGCCACTGGGCTCCAGATTTGGGAGCCACAGGGCCAACTGGAGCCTGGCGGAGACCCTACTGCCCTTCTCCTGCTCTAGAGTCCCTCCCTACGAGCAGGTGGCAGGCTGTGGCTTGGAGAGCCCCTGACACTGGGGCTCCCTCCCTCATCTCCCTCTGCCCAGCAATCTGTAGTGACTCTGGGTAGTGCTATTAACATGTCCTTCCAGGGGCTGAGCTGAGCTCACCTTCTTGTTGCTTCCCCCAGGGCCTGGCTGTGCCTCTGGGGGCCACAGAGACTCTGTCTGCCACAAGACAGTGCCTCAGAATTGGTGAGGCAAAGTCAGGCTCCCCTCTTAGTCCCTGCAGTTTGCTCTTTCTCTCAGCTGTGCACCTGTGATGCTTCCACACGCTCCTGTGGTAAGCTTTCTGGACCCTTCCTTAGCCCTATGACTCCCTGAGCCACTCTCCAGTTTGGTGGTTTCCTTTGAAGAGGGTGTGGCCAGGGAAGGAATGGAACCTAAGGAGTTGGTGGAGACCAGCTGCTTCTGCTCCAGCACTTAGGGGATCCATCATCTTCTCACGATGCTGAGGGCTGGAGAGGCTTTTGGCAACCAAATTGTACTCCATGGGCTAGAGCGCTGGAGCACGGGGCATCAGGAGAGAGGGCCCTTCCTGAATGGGCTGCAGTTTCCCAGTAACTTTCCAGGAGGTTACTGCAAGTGACAGCAGGGACCAGGCTGGGAGTCACAAGGTTCTGGGATGGTGAGGGCCTGAAGCATTCTTCCTCCGCTGCCTTATTGGAGGGTGCTGCCCCTCCCGAGCACCTTGCTGCACCTGCTCCTGAGTGCACAGGCTTTGAGCTTGAATCCTGGACGCATGAAACTAGCCGTGTGAACTGCAAGTTCCTCAGCCTTCCTGAGTCTTGCTTTTATCTCTTTTGTTAAAAGAGAAAATATCCGCTGGCCCGGGTCACTGTGCATTGAGTGGAATCTGATTTGTCAAGGGCTGGGCATAGGGGTGCAACACAGGAAACTTCGACTGCCCCCCTGTCTGCCATCTGTGTGCACTCTACAGCAAAAGCTTTATTTTTAGCAGGGGTACCCAAGATCTGGTGGTGGCCATTCAGCAGATGGTGCTAGTACCAAAGCTAGAACTCAATCACTGTTTGCCAGTGTGGGCATCATCCCCTGCAGATACCAGGAAGAGCAGCAGGCATAGATGCAAGGCCTGGGGGTCCAGGGCGATGGAGCCTCCCCTCAGGGGTGGGTGGGGTCCACGATGTGTGTGGGGGGGTGACTGGGAGCCCCAGGATGTGTTTCGCCAGTCCTAATTCAGCAGGAGCATTTGGATAAATCTTAGAACGATCTATCCTTCCACTCCCACCACTTCCCTCCCTAGAATCTCTCCTTACATCTGGCCCTATGCCCACACATCCTGAGTCATTAGTGGGGCTTCTCTGAATTTCCCTCCTTCTCTTAGAGGTGTGGGCACTGTCTGTTCATCCTTTTGGCATGAGGCTGCTCTCCTGGCATCCTTTGCCCTCAGTTGCTTCCCCAAATTGGCCCTGAAAAGTTTCCCAGGCAGGGTTGGGGCTTGCCAGACTGTGCAGTAGGCAGAAGGATAGGCAGAGACCACAGCTCTTCCAACAGCCCAGGGTCAATATCAGGCTGATGGTGTGAGAAAGTCCCATACAGGCCCATCTGCCCTCCTGCTCTTCCTTCCCCGCTTTGTGCGCTCAGTCTGTTGGGAGATGTAGGGGAGACGCAACGGGGCTCTGCCCTGAGATGGACCTGAGGTTACTGAGTCCTCGGGAGGAAGCCAAGAGCTGAGTCCGGGGCACCCACCAAAATAAGACCTGGAGCCTGGGTAGTGGGTGACATCTGCACCCTGGGGCCTTGCAGGGCCAGGCAGGAGATGGCAGAGCTGCGTCCAAGCCATGGACCCATGGGGTCAGCAGGGCGGGACAGGAGTGACTTCTCCTGCCAGGGTAGCACTGGTGGGGGTGACCCTCCTTACTGGGCTGGCTCTCCAGATTTTCTCCTATCCCACAAATCTGCGGCAGAGCTCTCGGGTCTCTCCACGTGGTCACCCACCATCTATTGTCCCCACTCTGGTGGTCAAAGTCTCTACTCTCTGACCCCAGCCCTGGTCTTACATCTGCTACACTATTTGCTGTGCCTGCATTTCTCCCAAAGAACACTAGCTGTTAATTAAACATTTGCTGACATGGATCCTGCTAGACATTGAGGGTGTGTGTGTGTGGGGTGGGGGTGGGGGCCATGGGGAGAGAAACATTAGTCCTGAGCTGATACTTCCCAAATACACCTTTTCCCACTTCCCTTGTCCTTGCACATGCTGTGCTTTCTGTTCCAGATGCTCTTCTCCCCACTGTGTGTGTCTGGCTCTAAAAAATGCTCCCTTGTCCCCAGGTCCAGCTCAAATGCCACCTCCCCAATCCCTGTGAGAGGGACATTCCCTCCCATGGTACCTGTCTTGCTTCTTTTTGTTTTTTTTTTGTTTTTCTGAGATGGAGTCTCACTTTATCGCCCAGGCTGGAGTACAGTGGCACAATCTCAGCTCACTGTAACCTCCGCCTCCTGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGATTACAGGAGCGTGTCATCACACCCAGCTAATTTTTGTATTTTTGTAGAGATAGTGTTTTGCCACATTGGTCAGGCTGGTGTTTAACTCCTGACGTCAGGTGATCCGCCTACCTTGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACTGCGCCCGGCCCCTGTCCTGCTTCTGATCACAGTTTGCGCAGGGTCTATTAGGATCCAGCCCTTCTCCCTTCCCCAGCCCCTCCTCTCCTGTGAAAGCCTGGGGGAACAGACATCTACACTGGTTGACTTGGATGTGTGTTTTATACAAAAATGTGTATGCTGTATACCCAGTTCACAGTGCAGAAAGTATGTTTTGTAAACTTGGCTTCCCTTGTATGTATCTGTTTGGGCTCTGGCCTGCTGGGCGATCAGTTTTGGTTTTCCTTCGGTTTGGGGCGGTGGGAGGGAGAAGTGCTAGAAATTCCTGCTGTTCACTTCCAGTTTCCTGGAGAACTTGTTAAAATACAAAGTGCTGGATCCACCCTAGATCTCTACATATTCCTGCTTCCATCCCAAT", "alternate_allele_vcf": "AGAGATCCA"}, {"assembly": "GRCh37", "chr": "7", "accession": "NC_000007.13", "start": 30999250, "stop": 31006943, "display_start": 30999250, "display_stop": 31006943, "variant_length": 7694, "alternate_allele": "AGAGATCCA", "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 30999250, "reference_allele_vcf": "TTGCCAGTACAATGTTGAAGACAAAGCATGATCAAAGCAATGACTACAAAGAGGTAGAAGTGGTCCTGTCAAAGCAAAAGCAGACCGGTCAAGAGCAAAATTCATGATGAAAACAGTTTTGGGGATGCTTGAGGTATTTTGCAGGTTGACTTTCTGGGGAGCCAAAGAACGATAACATCTGCTTATTGTGAAAATGTTTTGAGATAGCCAAAGCTTTAGCAGAAAAATGCCCAGGAAACCTTCACTAGAGAATCCTTCTCCACCACCACAATACTCCTGTTCATTCTTCTCATCAAACAAGGCCAGTTTTGCGAGAGTTTTGATAGGAAATCATTACACATCCACCTCACAGCCATGATTTGGCTTTTCATGATGTCTTTTTGTTTTCTAATCTTAAAAAATCTTTTAAGGGCACTCATTTTTCTTTAGGTAGTAATGTAAAAAAGACTGCATTGACATGGCTAAATTCCCAGGACTCTCAGTGTTTTAGGGATGGATTACATGGTTGGTATCATTGCTTACAAAAGTGTCTTGAAAGCTTATGTTGAGAAATAAAGTTTATATTTTTTATTTTTTAATTCCATATTTCCATGAACTTTGTGAAATCCTCTTGTACAAATAGATTTAGTTCATACCTTTTAACCGCTCAGTAGTATTCCATTGTATGAATAGATCACATTTTGTTTAGCTATTCCTTTCTCATTGGACAATTGTGTTGTTTTCTGGTTTTTACTACATGTTATAAACAACACTGAACTCAGAACGCAAATACCCAGAACTGGAATTTCTGGCTTATAGGGTATGTTCATTCTTAAATTCATTAGATAATATCAAATTGTTTTTCAAAGTGGTTATACAAAATTCACTCTCATCTGCCATTTATGAATGCTCCCATTTCTTTACATTATCTTCCAGACACTGTGTTATCAGACATTAAAGTTTTAGGCAATGTATTAGGTGAAAATGGGTAGCTTATTATTATTTTTATTTTCATATTCTTTAGTATTAGGAATGTTAAACATTTCTTCATCTGTTTATTGGCCTGTATATTTCACTTCTTTTCTGAATTGTCTATTTGTATCATTTGCTCACTTTTCTGAGTTATTTTTATCTTTCTTACTGATTTTTTTCTCTTCTTTCTTTTTTTTTTTGTGACATAGTCTCACTCTGTTGCCCAGGCTGGAGTGCAGTGGCACGATCTTGGCTTACTGCAGACTCCACCTCCCAGGTTCAAGGGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGAACTACAGTTGTGCACCACCAGGCCTGGCTAATTTTTGTATTTTCAGTAGAGACAAGGGTTCACCATATTGGCCAGGCTGACCTGGTGATCCGCCCGCCTTGGCCTCCCAAAGTGCTGGGATTACTGGCGTGAGCCACCACGACCAGCTGATTTTTAGATATTTTTAAAATACATTTTTGATACTACAGATTTGTTTGTCAGGATTGGTTGCAAATATTTCTTTCAGTTTGTAGCAGAAAAATGCTTTTAGTTTTCATCTATGGCATCCTCTCTTGAACATACATTTTAAAATGTTAATGTGGTCACACTTGATTTTTTTCTTTACGATTTTTATTTTATATGACACTCTCCTTTATTCTAAGGCCATAAACATGAATTTCTATTTTTTGAAGCATTTTTATGATTTTGTTGTTTTATAATTAGGATTTTTAACCTAGAATCTATATTTTGTAAATGTGAGCTAGAGATTCAATCTTATTTTTTTGTACAAAGAATCAGCTGTTCCAATCTTACTTGCTGTTAGTCCATCTTTGTTACATGCTGTCATAAATGATTGCCCACTGGATCTAGGCTCTGTATGAGGTTCTTTATAGTACACGGCTTTCCTTGTCCACTTATCCCACCAATCCTATAAGGAAGGTGTTAGTATCATCCCCACTTTTCAGATGGGAAAACGGAGGCTCATATGGTTTGAATGTTTTGTTCTCTCCAAATCTTATGTTGAAATAGACCTGCATTGTTGGAGGTGGGGCCTGGTGGGAGGTGTTTGCGTCATGGGGGTGGGTCCCTCATGAATGGCTTGGTGCCCTCCCCATGGTAATGAGTGAGTTCTCACTCTGCTAGTTCATGCAAGAGTTAGTAGTTTTAAAGAGCCAGCCAGACATCTCCCTTGCTCTCTTGCTCCCTCTCTCACCATGTGATACACCAGGGGTTCCCCCTTCACCTTCCAGCATGAATGGAAGCTTCTTGAGGCCCTCACCAGAAGCAGATGCCAGTGCCATGCTTCCTGTGCAGTCTGCAGAACTGTGAGCCGCAATAAACCTCTTTTTAAAAATATAATACCAAGCCTTGGGTATTCCCTTATAGCAATACAAATGTACTAACACAGAGGTTCAGAAAGGCTAAATGACTTGCCAAATGTATGACAGCTAGCAAGTGATGGAGGCAGAATTTGAATCCTGAGTGTATACAGAATTAGCTAGAGAAGACAGCTCCATGAAGAAACAGGCCTGCAGGGATCCTTGGGGAACATGTACAGTTAGAGCAGGGTTTCTCAGCCTTGGTCTTATTGATCTTTGAGACTGGATAATTCTTCATATGATCAAGGGTGGGGGCATCCTGTGCATTGTAGATGCTTAATAGCATCCCTGGTCTCTACTCATTCGATACCAGGAGCAACTCACCACCCCACTCCTCACCCTAACTCCTAGTTTTTATTTTGATAACAAAAAATGTCTCCAGACATTGCCAAATGTCCCCTAGGGAAGCAAAATTGCTCCAGGTTAGGAACCACTCGTTTAGACAGTAATAACTATTATTAATTATCACTATCAACCTCAATAATTAGCCATCATTAATGCTAATGATATTGATGCTAATTATCAACAGTGATTAATCGTAAGACTTTTTTTTCCTGGTGCTGTTGCTTCTTTGTAGCTGAGGAACAGAAGGTTCTAGCTTTCCCTTCAAGTTATACCTTTTCAGCACTCTGCTTTTCCAACCCGTGAGCTCTCAGCCTGCCAAGAGAGGAGCTCTGCTCTCCCCTAAAAGTGTAAAAGTGTGCAGAGCTCTGTGTGGCATGCTGCTTGCACCCATTTCACAGTTAAGCTCATGAAAACACTTGCACAGGATAGGAGGGTTTTGGAGCTTGGGGTGGTTCATGTTTTTGTTTCGAAATATTTTTTTTTCAGTATTTTGTTGACAATGAAGAAAAATGGAAAAATAAACCCCTGCTGATGTCAAAATAAGCCCTAAATCCAGATGTAGCGGGGGCGAGGAGCCTTCAACATTCATGATGTGATCGGGCTGTAAACATGTCTGGTGTTCTAGCACGCAGCCCAGCAGCTTCTGTGAGTGGAGACGTGCACACAAACATCAGGACCTGTCGGCTACTGGGATATTCAGGTCTTTCAGAGGTGACATCTTTGACATTTCAAAGTGCTGTGCAAGATCCAGGGGCATTTAGAACACTGTCTTTAGCCTGGCCAATGGAGACCCTGCATTTTAAAGTCTAAAACTATAATAAAAGTGACCAGGCAATGAATGTTCAATATAGTTTGCTGTGTAAGTCTTCTCATTTCTGCTACCGATGAGAGTTGTCCTCCCCCTATTCAAGATGGCTTGACCCATGAATCCTTCACAAGGCTTCCAACCAACCTCATTTTCCCCTTTTGCCGTGAGAGTTTTGGAGAGATTTTGATAAGCCCCCATGTGAAATCCAGAGCCTTGATGCTTGCAGCTTCAGCTCACCATCCAGGCCAGCGTCCTTGCCCAGTAAAGGACCCAGGTCTTGCTGAAATGACACATTCCTGGCCAGCCCATGCCAGTGCTTACAGATCATACTTCCTTTCCTAAGACCATTCCAACCCTCCATCTCCACTAATACCATACCCTTCCCCTTCCCCACCAGTTCCACACAGCTCTGACCTCACTCTCCAGCCCTGTGGATGAGGCTAGGAGCACACATCAAATAACCTGGGAGCTTCCCAAGGGCAGGCCCAGGTCCCCTTCCTATTCTTTAAGATCCCATCAATCTGAGGGGTCACTCCAATGATGGCCACCAGAGACCTGGGCTTAGAGAAGAAAGTGGTAGAGAATATTGACCAAGTGACCTGTGGCTGTCACCTCTCTGGGCCCTTGCTATCAGGACAGACACACAAGCAGACTTATAGCCAGAGTAGAAGGCGATGAGGGTGGGGGCTCAGCCCCTGCCTGCTGGAAACAGAGTCCCACCTCAGGGTCAATGCTGAGCTGGGCAGGTGTCCTGCAATCCTGGTGAATATTCAGCGGTCTGTGTCCCCTTGGCTAGCTCCTGCCTATGCAAACAGCCACCTGAGAAGGGGAAGCAGAGGGTGCGGTGGAAACGGCTGTGTCAGGGGACAGCAGGGGAAGGAAGATAGCCAAGGCTTACTGAGGCTGGTGGAGGGAGCCACTGCTGGGCTCACCATGGACCGCCGGATGTGGGGGGCCCACGTCTTCTGCGTGTTGAGCCCGTTACCGACCGTGAGTAGCCAGCTGAGACCCTCTGGCCTCTGCCACTGGGCTCCAGATTTGGGAGCCACAGGGCCAACTGGAGCCTGGCGGAGACCCTACTGCCCTTCTCCTGCTCTAGAGTCCCTCCCTACGAGCAGGTGGCAGGCTGTGGCTTGGAGAGCCCCTGACACTGGGGCTCCCTCCCTCATCTCCCTCTGCCCAGCAATCTGTAGTGACTCTGGGTAGTGCTATTAACATGTCCTTCCAGGGGCTGAGCTGAGCTCACCTTCTTGTTGCTTCCCCCAGGGCCTGGCTGTGCCTCTGGGGGCCACAGAGACTCTGTCTGCCACAAGACAGTGCCTCAGAATTGGTGAGGCAAAGTCAGGCTCCCCTCTTAGTCCCTGCAGTTTGCTCTTTCTCTCAGCTGTGCACCTGTGATGCTTCCACACGCTCCTGTGGTAAGCTTTCTGGACCCTTCCTTAGCCCTATGACTCCCTGAGCCACTCTCCAGTTTGGTGGTTTCCTTTGAAGAGGGTGTGGCCAGGGAAGGAATGGAACCTAAGGAGTTGGTGGAGACCAGCTGCTTCTGCTCCAGCACTTAGGGGATCCATCATCTTCTCACGATGCTGAGGGCTGGAGAGGCTTTTGGCAACCAAATTGTACTCCATGGGCTAGAGCGCTGGAGCACGGGGCATCAGGAGAGAGGGCCCTTCCTGAATGGGCTGCAGTTTCCCAGTAACTTTCCAGGAGGTTACTGCAAGTGACAGCAGGGACCAGGCTGGGAGTCACAAGGTTCTGGGATGGTGAGGGCCTGAAGCATTCTTCCTCCGCTGCCTTATTGGAGGGTGCTGCCCCTCCCGAGCACCTTGCTGCACCTGCTCCTGAGTGCACAGGCTTTGAGCTTGAATCCTGGACGCATGAAACTAGCCGTGTGAACTGCAAGTTCCTCAGCCTTCCTGAGTCTTGCTTTTATCTCTTTTGTTAAAAGAGAAAATATCCGCTGGCCCGGGTCACTGTGCATTGAGTGGAATCTGATTTGTCAAGGGCTGGGCATAGGGGTGCAACACAGGAAACTTCGACTGCCCCCCTGTCTGCCATCTGTGTGCACTCTACAGCAAAAGCTTTATTTTTAGCAGGGGTACCCAAGATCTGGTGGTGGCCATTCAGCAGATGGTGCTAGTACCAAAGCTAGAACTCAATCACTGTTTGCCAGTGTGGGCATCATCCCCTGCAGATACCAGGAAGAGCAGCAGGCATAGATGCAAGGCCTGGGGGTCCAGGGCGATGGAGCCTCCCCTCAGGGGTGGGTGGGGTCCACGATGTGTGTGGGGGGGTGACTGGGAGCCCCAGGATGTGTTTCGCCAGTCCTAATTCAGCAGGAGCATTTGGATAAATCTTAGAACGATCTATCCTTCCACTCCCACCACTTCCCTCCCTAGAATCTCTCCTTACATCTGGCCCTATGCCCACACATCCTGAGTCATTAGTGGGGCTTCTCTGAATTTCCCTCCTTCTCTTAGAGGTGTGGGCACTGTCTGTTCATCCTTTTGGCATGAGGCTGCTCTCCTGGCATCCTTTGCCCTCAGTTGCTTCCCCAAATTGGCCCTGAAAAGTTTCCCAGGCAGGGTTGGGGCTTGCCAGACTGTGCAGTAGGCAGAAGGATAGGCAGAGACCACAGCTCTTCCAACAGCCCAGGGTCAATATCAGGCTGATGGTGTGAGAAAGTCCCATACAGGCCCATCTGCCCTCCTGCTCTTCCTTCCCCGCTTTGTGCGCTCAGTCTGTTGGGAGATGTAGGGGAGACGCAACGGGGCTCTGCCCTGAGATGGACCTGAGGTTACTGAGTCCTCGGGAGGAAGCCAAGAGCTGAGTCCGGGGCACCCACCAAAATAAGACCTGGAGCCTGGGTAGTGGGTGACATCTGCACCCTGGGGCCTTGCAGGGCCAGGCAGGAGATGGCAGAGCTGCGTCCAAGCCATGGACCCATGGGGTCAGCAGGGCGGGACAGGAGTGACTTCTCCTGCCAGGGTAGCACTGGTGGGGGTGACCCTCCTTACTGGGCTGGCTCTCCAGATTTTCTCCTATCCCACAAATCTGCGGCAGAGCTCTCGGGTCTCTCCACGTGGTCACCCACCATCTATTGTCCCCACTCTGGTGGTCAAAGTCTCTACTCTCTGACCCCAGCCCTGGTCTTACATCTGCTACACTATTTGCTGTGCCTGCATTTCTCCCAAAGAACACTAGCTGTTAATTAAACATTTGCTGACATGGATCCTGCTAGACATTGAGGGTGTGTGTGTGTGGGGTGGGGGTGGGGGCCATGGGGAGAGAAACATTAGTCCTGAGCTGATACTTCCCAAATACACCTTTTCCCACTTCCCTTGTCCTTGCACATGCTGTGCTTTCTGTTCCAGATGCTCTTCTCCCCACTGTGTGTGTCTGGCTCTAAAAAATGCTCCCTTGTCCCCAGGTCCAGCTCAAATGCCACCTCCCCAATCCCTGTGAGAGGGACATTCCCTCCCATGGTACCTGTCTTGCTTCTTTTTGTTTTTTTTTTGTTTTTCTGAGATGGAGTCTCACTTTATCGCCCAGGCTGGAGTACAGTGGCACAATCTCAGCTCACTGTAACCTCCGCCTCCTGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGATTACAGGAGCGTGTCATCACACCCAGCTAATTTTTGTATTTTTGTAGAGATAGTGTTTTGCCACATTGGTCAGGCTGGTGTTTAACTCCTGACGTCAGGTGATCCGCCTACCTTGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACTGCGCCCGGCCCCTGTCCTGCTTCTGATCACAGTTTGCGCAGGGTCTATTAGGATCCAGCCCTTCTCCCTTCCCCAGCCCCTCCTCTCCTGTGAAAGCCTGGGGGAACAGACATCTACACTGGTTGACTTGGATGTGTGTTTTATACAAAAATGTGTATGCTGTATACCCAGTTCACAGTGCAGAAAGTATGTTTTGTAAACTTGGCTTCCCTTGTATGTATCTGTTTGGGCTCTGGCCTGCTGGGCGATCAGTTTTGGTTTTCCTTCGGTTTGGGGCGGTGGGAGGGAGAAGTGCTAGAAATTCCTGCTGTTCACTTCCAGTTTCCTGGAGAACTTGTTAAAATACAAAGTGCTGGATCCACCCTAGATCTCTACATATTCCTGCTTCCATCCCAAT", "alternate_allele_vcf": "AGAGATCCA"}], "measure_relationship": [{"type": "genes overlapped by variant", "names": [{"value": {"type": "Preferred", "value": "growth hormone releasing hormone receptor"}}], "symbols": [{"value": {"type": "Preferred", "value": "GHRHR"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "7", "accession": "NC_000007.14", "start": 30963953, "stop": 30979528, "display_start": 30963953, "display_stop": 30979528, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "7", "accession": "NC_000007.13", "start": 31003635, "stop": 31019145, "display_start": 31003635, "display_stop": 31019145, "strand": "+", "variant_length": 15511, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "2692"}, {"db": "OMIM", "id": "139191", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:4266"}]}], "comments": [{"text": "Deletion of exon 1 from GHRHR plus flanking intronic sequences.", "type": "public", "datasource": "NCBI curation"}], "id": 71561}], "names": [{"value": {"type": "Preferred", "value": "Single allele"}}], "xrefs": [{"db": "ClinGen", "id": "CA144520"}], "id": 56966}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Isolated growth hormone deficiency type IB"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0013006"}]}, {"value": {"type": "Alternate", "value": "IGHD IB"}, "xrefs": [{"db": "OMIM", "id": "612781", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Isolated growth hormone deficiency type 1B"}, "xrefs": [{"db": "Genetic Alliance", "id": "Isolated+growth+hormone+deficiency+type+1B/3883"}]}, {"value": {"type": "Alternate", "value": "IGHD 1B"}}], "symbols": [{"value": {"type": "Preferred", "value": "IGHD1B"}, "xrefs": [{"db": "OMIM", "id": "612781", "type": "MIM"}]}], "attributes": [{"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "3919"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0013006"}, {"db": "MedGen", "id": "C2748571"}, {"db": "Orphanet", "id": "631"}, {"db": "OMIM", "id": "612781", "type": "MIM"}]}], "id": 5192}, "date_created": "2013-09-05", "date_last_updated": "2022-06-05", "id": 133514}, "record_status": "current", "title": "Single allele AND Isolated growth hormone deficiency type IB", "clinvar_assertions": [{"id": 133513, "submission_id": {"local_key": "Indel -1", "submitter": "Endocrinology Clinic, Seth G.S. Medical College", "submitter_date": "2013-11-13"}, "clinvar_accession": {"acc": "SCV000082856", "version": 2, "type": "SCV", "date_updated": "2013-09-05", "date_created": "2013-09-05", "org_id": "500130", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "comments": [{"text": "Converted during submission to Pathogenic."}], "date_last_evaluated": "2013-04-22"}], "external_ids": [{"db": "Department of Endocrinology, Seth G.S. Medical College and K.E.M. Hospital", "id": "Indel -1"}], "attributes": [{"attribute": {"type": "ModeOfInheritance", "value": "Autosomal recessive inheritance"}}], "observed_in": [{"sample": {"origin": "inherited", "tissue": "blood", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "gender": "mixed", "family_data": {"family_history": "yes", "num_families": 2, "num_families_with_variant": 2, "num_families_with_segregation_observed": 2}}, "methods": ["case-control"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 6}}, {"attribute": {"type": "Homozygote", "integer_value": 3}}, {"attribute": {"type": "SingleHeterozygote", "integer_value": 3}}, {"attribute": {"type": "CompoundHeterozygote", "integer_value": 1}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NC_000007.13:g.30999250_31006943delinsAGAGATCCA"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "GHRHR"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "Isolated growth hormone deficiency type 1B"}}], "xrefs": [{"db": "OMIM", "id": "612781", "type": "MIM"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000416351", "version": 3, "type": "RCV", "date_updated": "2022-09-24", "date_created": "2017-01-30"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "likely pathogenic", "date_last_evaluated": "2016-01-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "number_tested": 1}, "methods": ["research"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}, {"attribute": {"type": "FamilyHistory", "value": "yes"}}]}], "measures": {"type": "Variant", "acc": "VCV000375296", "version": 3, "measures": [{"type": "deletion", "names": [{"value": {"type": "Preferred", "value": "NM_020964.3(EPG5):c.4665del (p.Glu1555fs)"}}], "canonical_spdi": "NC_000018.10:45899547:TT:T", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_1234t1:c.4665del"}, {"type": "HGVS, coding, RefSeq", "value": "NM_020964.3:c.4665del"}, {"type": "HGVS, genomic, LRG", "value": "LRG_1234:g.72792del"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_042838.1:g.72792del"}, {"type": "HGVS, genomic, top level", "value": "NC_000018.10:g.45899549del", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000018.9:g.43479514del", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_020964.2:c.4665delA"}, {"type": "HGVS, protein", "value": "LRG_1234p1:p.Glu1555fs"}, {"type": "HGVS, protein, RefSeq", "value": "NP_066015.2:p.Glu1555fs"}, {"type": "MolecularConsequence", "value": "frameshift variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001589"}, {"db": "RefSeq", "id": "NM_020964.3:c.4665del"}]}, {"type": "ProteinChange1LetterCode", "value": "E1555fs"}], "cytogenic_locations": ["18q12.3"], "sequence_locations": [{"assembly": "GRCh38", "chr": "18", "accession": "NC_000018.10", "start": 45899548, "stop": 45899548, "display_start": 45899548, "display_stop": 45899548, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 45899547, "reference_allele_vcf": "AT", "alternate_allele_vcf": "A"}, {"assembly": "GRCh37", "chr": "18", "accession": "NC_000018.9", "start": 43479513, "stop": 43479513, "display_start": 43479513, "display_stop": 43479513, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 43479512, "reference_allele_vcf": "AT", "alternate_allele_vcf": "A"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "ectopic P-granules 5 autophagy tethering factor"}}], "symbols": [{"value": {"type": "Preferred", "value": "EPG5"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "18", "accession": "NC_000018.10", "start": 45800581, "stop": 45967329, "display_start": 45800581, "display_stop": 45967329, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "18", "accession": "NC_000018.9", "start": 43427573, "stop": 43547304, "display_start": 43427573, "display_stop": 43547304, "strand": "-", "variant_length": 119732, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "57724"}, {"db": "OMIM", "id": "615068", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:29331"}]}], "xrefs": [{"db": "dbSNP", "id": "1057519318", "type": "rs"}], "id": 362072}], "names": [{"value": {"type": "Preferred", "value": "NM_020964.3(EPG5):c.4665del (p.Glu1555fs)"}}], "xrefs": [{"db": "ClinGen", "id": "CA16044048"}], "id": 375296}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Vici syndrome"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0009452"}]}, {"value": {"type": "Alternate", "value": "Absent corpus callosum cataract immunodeficiency"}, "xrefs": [{"db": "Genetic Alliance", "id": "Absent+Corpus+Callosum+Cataract+Immunodeficiency/81"}]}, {"value": {"type": "Alternate", "value": "Immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum"}}], "symbols": [{"value": {"type": "Preferred", "value": "VICIS"}, "xrefs": [{"db": "OMIM", "id": "242840", "type": "MIM"}]}], "attributes": [{"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "448"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0009452"}, {"db": "MedGen", "id": "C1855772"}, {"db": "Orphanet", "id": "1493"}, {"db": "OMIM", "id": "242840", "type": "MIM"}]}], "id": 9271}, "date_created": "2017-01-30", "date_last_updated": "2022-09-24", "id": 966387}, "record_status": "current", "title": "NM_020964.3(EPG5):c.4665del (p.Glu1555fs) AND Vici syndrome", "clinvar_assertions": [{"id": 966323, "submission_id": {"local_key": "chr18:43479512delT", "submitter": "Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS", "submitted_assembly": "GRCh37", "submitter_date": "2016-12-19"}, "clinvar_accession": {"acc": "SCV000494026", "version": 1, "type": "SCV", "date_updated": "2017-01-30", "date_created": "2017-01-30", "org_id": "505641", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["likely pathogenic"], "date_last_evaluated": "2016-01-01"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "ACMG Guidelines, 2015"}, "citations": [{"ids": [{"source": "PubMed", "value": "25741868"}]}]}], "observed_in": [{"sample": {"origin": "germline", "geographic_origin": "India", "tissue": "amniotic fluid", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "number_tested": 1, "family_data": {"family_history": "yes"}, "proband": "yes"}, "methods": ["research"], "observed_data": [{"attribute": {"type": "Homozygote", "integer_value": 1}}], "comments": [{"text": "First child was similarly affected and expired. The present subject was a fetus of 19 weeks gestation, found similarly affected like the first child and the pregnancy was terminated. Fetus brought for autopsy and further genetic analysis."}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_020964.2:c.4665delA"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "EPG5"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "OMIM", "id": "242840", "type": "MIM"}]}]}, "study_description": "Identification of novel variants in Mendelian Disorders.", "comments": [{"text": "Indel variant"}]}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV001263497", "version": 1, "type": "RCV", "date_updated": "2022-11-19", "date_created": "2020-11-06"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "likely pathogenic"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "maternal", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}]}], "measures": {"type": "Variant", "acc": "VCV000983534", "version": 1, "measures": [{"type": "indel", "names": [{"value": {"type": "Preferred", "value": "NM_005559.4(LAMA1):c.8208_8214delinsT (p.Lys2736_Ser2738delinsAsn)"}}], "canonical_spdi": "NC_000018.10:6950964:CGAGAGC:A", "attributes": [{"type": "FunctionalConsequence", "value": "functionally_abnormal", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0002218"}]}, {"type": "HGVS, coding", "value": "NM_005559.4:c.8208_8214delGCTCTCGinsT"}, {"type": "HGVS, coding, RefSeq", "value": "NM_005559.4:c.8208_8214delinsT"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_034251.1:g.171844_171850delinsT"}, {"type": "HGVS, genomic, top level", "value": "NC_000018.10:g.6950965_6950971delinsA", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000018.9:g.6950964_6950970delinsA", "integer_value": 37}, {"type": "HGVS, protein", "value": "p.Lys2736_Leu2737del"}, {"type": "HGVS, protein, RefSeq", "value": "NP_005550.2:p.Lys2736_Ser2738delinsAsn"}, {"type": "MolecularConsequence", "value": "inframe_indel", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001820"}, {"db": "RefSeq", "id": "NM_005559.4:c.8208_8214delinsT"}]}], "cytogenic_locations": ["18p11.31"], "sequence_locations": [{"assembly": "GRCh38", "chr": "18", "accession": "NC_000018.10", "start": 6950965, "stop": 6950971, "display_start": 6950965, "display_stop": 6950971, "variant_length": 7, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 6950965, "reference_allele_vcf": "CGAGAGC", "alternate_allele_vcf": "A"}, {"assembly": "GRCh37", "chr": "18", "accession": "NC_000018.9", "start": 6950964, "stop": 6950970, "display_start": 6950964, "display_stop": 6950970, "variant_length": 7, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 6950964, "reference_allele_vcf": "CGAGAGC", "alternate_allele_vcf": "A"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "laminin subunit alpha 1"}}], "symbols": [{"value": {"type": "Preferred", "value": "LAMA1"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "18", "accession": "NC_000018.10", "start": 6941742, "stop": 7117797, "display_start": 6941742, "display_stop": 7117797, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "18", "accession": "NC_000018.9", "start": 6941742, "stop": 7117812, "display_start": 6941742, "display_stop": 7117812, "strand": "-", "variant_length": 176071, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "284217"}, {"db": "OMIM", "id": "150320", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:6481"}]}], "xrefs": [{"db": "dbSNP", "id": "2057544094", "type": "rs"}], "id": 971601}], "names": [{"value": {"type": "Preferred", "value": "NM_005559.4(LAMA1):c.8208_8214delinsT (p.Lys2736_Ser2738delinsAsn)"}}], "id": 983534}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0014419"}]}, {"value": {"type": "Alternate", "value": "Poretti-Boltshauser syndrome"}}], "symbols": [{"value": {"type": "Alternate", "value": "PTBHS"}, "xrefs": [{"db": "OMIM", "id": "615960", "type": "MIM"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0014419"}, {"db": "MedGen", "id": "C4014821"}, {"db": "Orphanet", "id": "370022"}, {"db": "OMIM", "id": "615960", "type": "MIM"}]}], "id": 17513}, "date_created": "2020-11-06", "date_last_updated": "2022-11-19", "id": 2846139}, "record_status": "current", "title": "NM_005559.4(LAMA1):c.8208_8214delinsT (p.Lys2736_Ser2738delinsAsn) AND Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome", "clinvar_assertions": [{"id": 2845766, "submission_id": {"local_key": "SUB8478928", "submitter": "Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn", "title": "SUB8478928", "submitted_assembly": "GRCh37", "submitter_date": "2020-11-06"}, "clinvar_accession": {"acc": "SCV001441583", "version": 1, "type": "SCV", "date_updated": "2020-11-06", "date_created": "2020-11-06", "org_id": "507028", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["likely pathogenic"], "comments": [{"text": "Two biparental heterozygous mutations in the gene LAMA1 were found, which can sufficiently explain the phenotype: GRCh37:Chr18:6949099C>T; rs764745270 LAMA1 NM_005559.4:c.8556+1G>A and GRCh37:Chr18:6950964CGAGAGC>A LAMA1 NM_005559.4:c.8208_8214delGCTCTCGinsT; (p.Lys2736_Leu2737del) Evaluation of c.8208_8214insT in LAMA1: The maternally inherited heterozygous Indel variant CGAGAGC>A at position 6950964 on chromosome 18 was covered with 145 reads and has an AAV of 48% in the index, while the mother has an AAV of 47 with a coverage of 43 reads. The cover with the father at this position is 51 Reads assigns 100% the reference allele. The deletion of the 6bp leads to the loss of two over highly conserved amino acids across many species Serine 2737 and leucine 2738 and the sense-altering variant at position 6950970 leads to the exchange of the also highly conserved amino acid over many species Lysine to aspartic acid at position 2736 in LAMA1. Bioinformatic prediction programs like Mutation Probe and GERP classify this variant as pathogenic one. According to ACMG guidelines, c.8208_8214insT is expressed in LAMA1 is classified as probably pathogenic. Classification according to ACMG guidelines of c.8208_8214insT in LAMA1: probably pathogenic - PM1: The variant is located in a mutation hotspot - PM2: The variant was not found in population genetic studies (such as GnomAD, Iranome, GME, 1kGP, etc.) observed. - PM3: In the recessively inherited Poretti-Boltshauser syndrome this variant is in trans with a pathogenic variant (c.8556+1G>A). - PM4: The protein length changes due to deletion in a non-repetitive region of LAMA1. - PP3: Bioinformatic prediction programs such as GERP and Mutation Scanner classify this variant as pathogenic."}]}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "ACMG Guidelines, 2015"}, "citations": [{"ids": [{"source": "PubMed", "value": "25741868"}], "type": "general"}]}], "observed_in": [{"sample": {"origin": "maternal", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "gender": "female"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "CompoundHeterozygote", "integer_value": 1}}], "traits": {"type": "Finding", "traits": [{"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0000750"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0001263"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0001290"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0001320"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0001249"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0002342"}]}, {"type": "Finding", "xrefs": [{"db": "HP", "id": "HP:0000407"}]}]}}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Alternate", "value": "p.Lys2736_Leu2737del"}}], "attributes": [{"type": "HGVS", "value": "NM_005559.4:c.8208_8214delGCTCTCGinsT"}, {"type": "FunctionalConsequence", "value": "functionally_abnormal", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0002218", "url": "http://www.sequenceontology.org/browser/current_svn/term/SO:0002218"}]}], "measure_relationship": [{"type": "variant in gene", "names": [{"value": {"type": "Preferred", "value": "laminin subunit alpha 1"}}], "symbols": [{"value": {"type": "Preferred", "value": "LAMA1"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "OMIM", "id": "615960"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000449494", "version": 2, "type": "RCV", "date_updated": "2022-12-17", "date_created": "2017-03-27"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "likely pathogenic", "date_last_evaluated": "2016-01-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "unknown", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "number_tested": 1}, "methods": ["research"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}, {"attribute": {"type": "FamilyHistory", "value": "no"}}]}], "measures": {"type": "Variant", "acc": "VCV000397570", "version": 2, "measures": [{"type": "indel", "names": [{"value": {"type": "Preferred", "value": "NM_024312.5(GNPTAB):c.3250-1_3250delinsAT"}}], "canonical_spdi": "NC_000012.12:101757656:GC:AT", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_024312.5:c.3250-1_3250delinsAT"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_021243.1:g.78210_78211delinsAT"}, {"type": "HGVS, genomic, top level", "value": "NC_000012.12:g.101757657_101757658delinsAT", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000012.11:g.102151435_102151436delinsAT", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_024312.4:c.3250-1_3250delinsAT"}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_024312.5:c.3250-1_3250delinsAT"}]}], "cytogenic_locations": ["12q23.2"], "sequence_locations": 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"12", "accession": "NC_000012.12", "start": 101745499, "stop": 101830959, "display_start": 101745499, "display_stop": 101830959, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "12", "accession": "NC_000012.11", "start": 102139274, "stop": 102224644, "display_start": 102139274, "display_stop": 102224644, "strand": "-", "variant_length": 85371, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "79158"}, {"db": "OMIM", "id": "607840", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:29670"}]}], "xrefs": [{"db": "dbSNP", "id": "1060499687", "type": "rs"}], "id": 384456}], "names": [{"value": {"type": "Preferred", "value": "NM_024312.5(GNPTAB):c.3250-1_3250delinsAT"}}, {"value": {"type": "Preferred", "value": "NM_024312.5(GNPTAB):c.3250-1_3250delinsAT"}}], "xrefs": [{"db": "ClinGen", "id": "CA16609426"}], "id": 397570}, "traits": {"type": "Disease", 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ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML III\u03b1/\u03b2 becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML III\u03b1/\u03b2 are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML III\u03b1/\u03b2."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1828"}]}, {"value": {"type": "keyword", "value": "GNPTAB-Related Mucolipidoses"}}, {"value": {"type": "keyword", "value": "Neoplasm"}}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "6749"}]}], "trait_relationships": [{"type": "co-occurring condition", "id": 70}], "citations": [{"ids": [{"source": "PubMed", "value": "20301728"}, {"source": "BookShelf", "value": "NBK1828"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0009650"}, {"db": "MedGen", "id": "C2673377"}, {"db": "Orphanet", "id": "576"}, {"db": "OMIM", "id": "252500", "type": "MIM"}]}, {"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Pseudo-Hurler polydystrophy"}, "xrefs": [{"db": "Genetic Alliance", "id": "Mucolipidosis+type+3A/4909"}, {"db": "SNOMED CT", "id": "65764006"}]}, {"value": {"type": "Alternate", "value": "ML III"}, "xrefs": [{"db": "OMIM", "id": "252600", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "ML III ALPHA/BETA"}, "xrefs": [{"db": "OMIM", "id": "252600", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Mucolipidosis type 3A"}}, {"value": {"type": "Alternate", "value": "ML 3 A"}}, {"value": {"type": "Alternate", "value": "Type III Mucolipidosis"}}, {"value": {"type": "Alternate", "value": "ML IIIA"}, "xrefs": [{"db": "OMIM", "id": "252600", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Mucolipidosis III Alpha/Beta"}, "xrefs": [{"db": "GeneReviews", "id": "NBK1875"}]}], "symbols": [{"value": {"type": "Preferred", "value": "ML3"}}], "attributes": [{"value": {"type": "public definition", "value": "GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis III\u03b1/\u03b2 (ML III\u03b1/\u03b2), and phenotypes intermediate between ML II and ML III\u03b1/\u03b2. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML III\u03b1/\u03b2 becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML III\u03b1/\u03b2 are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML III\u03b1/\u03b2."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1828"}]}, {"value": {"type": "keyword", "value": "GNPTAB-Related Mucolipidoses"}}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "3806"}]}], "trait_relationships": [{"type": "co-occurring condition", "id": 70}], "citations": [{"ids": [{"source": "PubMed", "value": "20301728"}, {"source": "BookShelf", "value": "NBK1828"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0018931"}, {"db": "MedGen", "id": "C0033788"}, {"db": "Orphanet", "id": "577"}, {"db": "OMIM", "id": "252600", "type": "MIM"}]}], "id": 9397}, "date_created": "2017-03-27", "date_last_updated": "2022-12-17", "id": 1039484}, "record_status": "current", "title": 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"India", "species": {"value": "human", "taxonomy_id": 9606}, "age": [{"age_unit": "years", "value": 0, "type": "minimum"}, {"age_unit": "years", "value": 9, "type": "maximum"}], "affected_status": "yes", "number_tested": 1, "gender": "female", "family_data": {"family_history": "no"}, "proband": "yes"}, "methods": ["research"], "observed_data": [{"attribute": {"type": "Homozygote", "integer_value": 1}}], "traits": {"type": "Finding", "traits": [{"type": "Finding", "names": [{"value": {"type": "Preferred", "value": "Global developmental delay"}}], "xrefs": [{"db": "HP", "id": "HP:0001263"}]}, {"type": "Finding", "names": [{"value": {"type": "Preferred", "value": "obsolete Mental retardation, in some"}}], "xrefs": [{"db": "HP", "id": "HP:0006877"}]}]}}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_024312.4:c.3250-1_3250delinsAT"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": 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(2001) demonstrated an insertion/frameshift, 1641insG, in the ELAC2 gene in a Utah family with 8 prostate cancer cases (HPC2; 614731) in 3 generations. Insertion of a nucleotide between residues 1641 and 1642 shifted the reading frame after leu547, leading to termination after the miscoding of 67 residues. The mutation segregated with disease in this family."}, "citations": [{"ids": [{"source": "PubMed", "value": "11175785"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000005057", "version": 1, "measures": [{"type": "duplication", "names": [{"value": {"type": "Preferred", "value": "NM_018127.6(ELAC2):c.1641dup (p.His548Alafs)"}}], "canonical_spdi": "NC_000017.11:12996564:C:CC", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001165962.2:c.1521dup"}, {"type": "HGVS, coding, RefSeq", "value": "NM_173717.2:c.1638dup"}, {"type": "HGVS, coding, RefSeq", "value": "NM_018127.7:c.1641dup"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_015808.1:g.26500dup"}, {"type": "HGVS, genomic, top level", "value": "NC_000017.11:g.12996565dup", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000017.10:g.12899882dup", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_018127.6:c.1641dupG"}, {"type": "HGVS, protein, 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"NC_000017.11", "start": 12996564, "stop": 12996565, "display_start": 12996564, "display_stop": 12996565, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 12996564, "reference_allele_vcf": "G", "alternate_allele_vcf": "GC"}, {"assembly": "GRCh37", "chr": "17", "accession": "NC_000017.10", "start": 12899881, "stop": 12899882, "display_start": 12899881, "display_stop": 12899882, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 12899881, "reference_allele_vcf": "G", "alternate_allele_vcf": "GC"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "elaC ribonuclease Z 2"}}], "symbols": [{"value": {"type": "Preferred", "value": "ELAC2"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "17", "accession": "NC_000017.11", "start": 12991612, "stop": 13018027, "display_start": 12991612, 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The mutation segregated with disease in this family."}, "citations": [{"ids": [{"source": "PubMed", "value": "11175785"}]}], "xrefs": [{"db": "OMIM", "id": "614731", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "ELAC2, 1-BP, 1641G"}}], "attributes": [{"type": "NonHGVS", "value": "1-BP, 1641G"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "ELAC2"}}]}], "xrefs": [{"db": "OMIM", "id": "605367.0003", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "PROSTATE CANCER, HEREDITARY, 2"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000014834", "version": 26, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2012-09-13"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a sporadic case of Pallister-Hall syndrome (PHS; 146510), previously described by Ozerov et al. 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The insertion was found to be identical to a region partially overlapping 2 mitochondrial tRNA genes, MTTS2 (590085) and MTTL2 (590055)."}, "citations": [{"ids": [{"source": "PubMed", "value": "12545275"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": "9148633"}], "type": "general"}]}]}, {"sample": {"origin": "not provided", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["curation"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000013823", "version": 2, "measures": [{"type": "insertion", "names": [{"value": {"type": "Preferred", "value": "NM_000168.5(GLI3):c.2770_2771insNC_012920.1:g.12243..12314"}}], "attributes": [{"type": "HGVS, non-validated", "value": "NM_000168.5:c.2770_2771insNC_012920.1:g.12243..12314"}, {"type": "HGVS, previous", "value": "NM_000168.3:c.2770_2771ins72"}], "cytogenic_locations": ["7p14.1"], "sequence_locations": [{"assembly": "GRCh38", "chr": "7", "accession": "NC_000007.14", "start": 41966302, "stop": 41966303, "display_start": 41966302, "display_stop": 41966303, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "7", "accession": "NC_000007.13", "start": 42005900, "stop": 42005901, "display_start": 42005900, "display_stop": 42005901, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "GLI family zinc finger 3"}}], "symbols": [{"value": {"type": "Preferred", "value": "GLI3"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "7", "accession": "NC_000007.14", "start": 41960949, "stop": 42264268, "display_start": 41960949, "display_stop": 42264268, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "7", "accession": "NC_000007.13", "start": 42000546, "stop": 42276617, "display_start": 42000546, "display_stop": 42276617, "strand": "-", "variant_length": 276072, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "2737"}, {"db": "OMIM", "id": "165240", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:4319"}]}], "xrefs": [{"db": "dbVar", "id": "nssv3761571"}, {"db": "dbVar", "id": "nsv1067831"}, {"db": "OMIM", "id": "165240.0011", "type": "Allelic variant"}], "comments": [{"text": "72-nt insertion of mtDNA into exon 15 of GLI3 (NG_008434.1)", "type": "public", "datasource": "NCBI curation"}, {"text": "Insertion of 72-nt mitochondrial sequence for tRNA Ser and tRNA Leu (see PMID 15739154).", "type": "public", "datasource": "NCBI curation"}], "id": 28862}], "names": [{"value": {"type": "Preferred", "value": "NM_000168.5(GLI3):c.2770_2771insNC_012920.1:g.12243..12314"}}], "id": 13823}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Pallister-Hall syndrome"}, "xrefs": [{"db": "Genetic Alliance", "id": "Pallister-Hall+syndrome/5543"}, {"db": "MONDO", "id": "MONDO:0007804"}, {"db": "SNOMED CT", "id": "56677004"}]}, {"value": {"type": "Alternate", "value": "Hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly"}}], "symbols": [{"value": {"type": "Preferred", "value": "PHS"}, "xrefs": [{"db": "OMIM", "id": "146510", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "PHS1"}}], "attributes": [{"value": {"type": "public definition", "value": "Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1465"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "7305"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301638"}, {"source": "BookShelf", "value": "NBK1465"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "PubMed", "value": "20301753"}, {"source": "BookShelf", "value": "NBK5192"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0007804"}, {"db": "MedGen", "id": "C0265220"}, {"db": "Orphanet", "id": "672"}, {"db": "OMIM", "id": "146510", "type": "MIM"}]}], "id": 3814}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 72337}, "record_status": "current", "title": "NM_000168.5(GLI3):c.2770_2771insNC_012920.1:g.12243..12314 AND Pallister-Hall syndrome", "clinvar_assertions": [{"id": 35089, "submission_id": {"local_key": "165240.0011_PALLISTER-HALL SYNDROME", "submitter": "OMIM", "title": "GLI3, 72-BP INS mtDNA, EX14_PALLISTER-HALL SYNDROME", "submitter_date": "2015-05-21"}, "clinvar_accession": {"acc": "SCV000035089", "version": 4, "type": "SCV", "date_updated": "2015-05-23", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2003-03-01"}], "external_ids": [{"db": "OMIM", "id": "165240.0011", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a sporadic case of Pallister-Hall syndrome (PHS; 146510), previously described by Ozerov et al. 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The insertion was found to be identical to a region partially overlapping 2 mitochondrial tRNA genes, MTTS2 (590085) and MTTL2 (590055)."}, "citations": [{"ids": [{"source": "PubMed", "value": "9148633"}]}, {"ids": [{"source": "PubMed", "value": "12545275"}]}], "xrefs": [{"db": "OMIM", "id": "146510", "type": "MIM"}, {"db": "OMIM", "id": "590085", "type": "MIM"}, {"db": "OMIM", "id": "590055", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "GLI3, 72-BP INS mtDNA, EX14"}}], "attributes": [{"type": "NonHGVS", "value": "72-BP INS mtDNA, EX14"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "GLI3"}}]}], "xrefs": [{"db": "OMIM", "id": "165240.0011", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "PALLISTER-HALL SYNDROME"}}]}]}}, {"id": 91018, "submission_id": 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The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop."}, "xrefs": [{"db": "GeneReviews", "id": "NBK164500"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "3786"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "24156116"}, {"source": "BookShelf", "value": "NBK164500"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0009660"}, {"db": "MedGen", "id": "C0086652"}, {"db": "Orphanet", "id": "582"}, {"db": "OMIM", "id": "253010", "type": "MIM"}]}], "id": 247}, "date_created": "2022-03-28", "date_last_updated": "2022-04-23", "id": 4124959}, "record_status": "current", "title": "Single allele AND Mucopolysaccharidosis, MPS-IV-B", "clinvar_assertions": [{"id": 4124547, "submission_id": {"local_key": "123", "submitter": "Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics", "submitted_assembly": "GRCh37", "submitter_date": "2022-03-20"}, "clinvar_accession": {"acc": "SCV002107169", "version": 1, "type": "SCV", "date_updated": "2022-03-28", "date_created": "2022-03-28", "org_id": "507039", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["likely pathogenic"], "comments": [{"text": "The GLB1 mRNA analysis demonstrated the inclusion of the 18 b.p. fragment of the intron 5 (NC_000003.11:g.33100082_33100099) r.552_553insCATTTCTACCATGGGAAG. Detected in-trans with the pathogenic c.808T>G (p.Tyr270Asp) variant."}]}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "ACMG Guidelines, 2015"}, "citations": [{"ids": [{"source": "PubMed", "value": "25741868"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "family_data": {"num_families_with_variant": 1}}, "methods": ["research"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}, {"attribute": {"type": "CompoundHeterozygote", "integer_value": 1}}]}], "measures": {"type": "Variant", "measures": [{"type": "complex", "attributes": [{"type": "FunctionalConsequence", "value": "effect on RNA splicing function", "xrefs": [{"db": "Variation Ontology", "id": "0397", "url": "http://www.variationontology.org/cgi-bin/amivario/term-details.cgi?term=VariO:0397"}]}], "sequence_locations": [{"assembly": "GRCh37", "chr": "3", "start": 33100045, "stop": 33100046, "variant_length": 2}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "GLB1"}}]}]}], "comments": [{"text": "Insertion of the processed pseudogene NPM1. Several events were detected in the inegration site: 1 - 16 b.p.target site duplication NC_000003.11:g.33100046_33100061dup. 2 - 1301 b.p. insertion of NPM1 cDNA (corresponding to NM_002520.7:c.-97_*319inv), flanked by the single guanine at the 5\u2019 end, acquired during capping, and polyA tail at the 3\u2019 end."}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "OMIM", "id": "253010", "type": "MIM"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000003352", "version": 5, "type": "RCV", "date_updated": "2022-06-30", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2009-11-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Muscular Dystrophy-Dystroglycanopathy (Congenital with Brain and Eye Anomalies), Type A, 4"}}, {"attribute": {"type": "Description", "value": "Kobayashi et al. (1998) found that 87% of mutant alleles causing the autosomal recessive disorder Fukuyama congenital muscular dystrophy (MDDGA4; 253800) carried an insertion of a 3,062-bp transposon, situated in the 3-prime UTR of the FKTN gene."}, "citations": [{"ids": [{"source": "PubMed", "value": "9690476"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "Most Japanese patients with the retrotransposal insertion in the FKTN gene share a common founder haplotype. By applying 2 methods for the study of linkage disequilibrium between flanking polymorphic markers and the disease locus, and of its decay over time, Colombo et al. (2000) calculated the age of the insertion mutation to be approximately 102 generations (95% CI: 86-117 g), or slightly less. The estimated age dates the most recent common ancestor of the mutation-bearing chromosomes back to the time (or a few centuries before) the Yayoi people began migrating to Japan from the Korean peninsula. FCMD was the first human disease known to be caused primarily by an ancient retrotransposal integration."}, "citations": [{"ids": [{"source": "PubMed", "value": "11153909"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "Kato et al. (2004) stated that 9 nonfounder mutations had been identified in Japanese FCMD patients. Severe phenotype was significantly more frequent in patients who were compound heterozygotes for a point mutation and the 3-kb founder insertion in the FKTN gene than in homozygotes for the founder mutation. The authors described a PCR-based diagnostic method for rapid detection of the insertion mutation. Using this method, they screened 18 FCMD patients and found 16 homozygotes and 2 heterozygotes for the insertion. In the general Japanese population, they found that 6 of 676 persons were heterozygous carriers. Furthermore, they found 3 homozygotes for the FCMD founder mutation among 97 patients who had been said to have probable Duchenne muscular dystrophy (310200) or Becker muscular dystrophy (300376) (DMD/BMD) without any mutation in the DMD gene (300377). On the other hand, there were no FCMD homozygotes but 4 heterozygous carriers among 335 patients with DMD mutations."}, "citations": [{"ids": [{"source": "PubMed", "value": "15103718"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "By sequence analysis, Watanabe et al. (2005) characterized the insertion mutation and found that it was enclosed by target-site duplications at both ends. They noted that the sequence motif was characteristic of a class of retroposon referred to as SINE-VNTR-Alu (SVA)."}, "citations": [{"ids": [{"source": "PubMed", "value": "16222679"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "Watanabe et al. 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Although the boy's parents were born in Henan and Shanxi Provinces and had no known Japanese ancestry, haplotype analysis showed that both mutant alleles were on Japanese-derived haplotypes."}, "citations": [{"ids": [{"source": "PubMed", "value": "19842201"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "Cardiomyopathy, Dilated, 1X"}}, {"attribute": {"type": "Description", "value": "In 6 Japanese patients from 4 families with dilated cardiomyopathy and mild or no limb-girdle involvement (CMD1X; 611615), Murakami et al. (2006) identified compound heterozygosity in all for the 3-kb retroposon insertion and another missense mutation: Q358P (607440.0010) or R179T (607440.0011), respectively."}, "citations": [{"ids": [{"source": "PubMed", "value": "17036286"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000003199", "version": 3, "measures": [{"type": "insertion", "names": [{"value": {"type": "Preferred", "value": "NM_006731.2(FKTN):c.*4392_*4393ins[AB185332.1]"}}, {"value": {"type": "Alternate", "value": "NM_006731.2:c.*4392_*4393insSVA"}}], "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_434t2:c.*4392_*4393ins[AB185332.1]"}, {"type": "HGVS, coding, RefSeq", "value": "NM_006731.2:c.*4392_*4393ins[AB185332.1]"}, {"type": "HGVS, protein"}, {"type": "nucleotide change", "value": "3-KB INS, SVA RETROTRANSPOSON INS"}], "cytogenic_locations": ["9q31"], "measure_relationship": [{"type": "asserted, but not computed", "names": [{"value": {"type": "Preferred", "value": "fukutin"}}], "symbols": [{"value": {"type": "Preferred", "value": "FKTN"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "9", "accession": "NC_000009.12", "start": 105558130, "stop": 105641118, "display_start": 105558130, "display_stop": 105641118, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "9", "accession": "NC_000009.11", "start": 108320410, "stop": 108403398, "display_start": 108320410, "display_stop": 108403398, "strand": "+", "variant_length": 82989, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "2218"}, {"db": "OMIM", "id": "607440", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:3622"}]}], "xrefs": [{"db": "Genetic Testing Registry (GTR)", "id": "GTR000325670"}, {"db": "OMIM", "id": "607440.0001", "type": "Allelic variant"}], "comments": [{"text": "Insertion of retrotransposal insertion sequence into 3'-UTR of FKTN.", "type": "public", "datasource": "NCBI curation"}], "id": 18238}], "names": [{"value": {"type": "Preferred", "value": "NM_006731.2(FKTN):c.*4392_*4393ins[AB185332.1]"}}, {"value": {"type": "Preferred", "value": "NM_006731.2(FKTN):c.*4392_*4393ins[AB185332.1]"}}], "id": 3199}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Dilated cardiomyopathy 1X"}, "xrefs": [{"db": "Genetic Alliance", "id": "Dilated+cardiomyopathy+1X/8262"}, {"db": "MONDO", "id": "MONDO:0012704"}]}, {"value": {"type": "Alternate", "value": "CARDIOMYOPATHY, DILATED, WITH MILD OR NO PROXIMAL MUSCLE WEAKNESS"}, "xrefs": [{"db": "OMIM", "id": "611615", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "FKTN-Related Dilated Cardiomyopathy"}}], "symbols": [{"value": {"type": "Preferred", "value": "CMD1X"}, "xrefs": [{"db": "OMIM", "id": "611615", "type": "MIM"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301486"}, {"source": "BookShelf", "value": "NBK1309"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0012704"}, {"db": "MedGen", "id": "C1969024"}, {"db": "Orphanet", "id": "154"}, {"db": "OMIM", "id": "611615", "type": "MIM"}]}], "id": 821}, "date_created": "2013-04-04", "date_last_updated": "2022-06-30", "id": 60855}, "record_status": "current", "title": "NM_006731.2(FKTN):c.*4392_*4393ins[AB185332.1] AND Dilated cardiomyopathy 1X", "clinvar_assertions": [{"id": 23510, "submission_id": {"local_key": "607440.0001_CARDIOMYOPATHY, DILATED, 1X", "submitter": "OMIM", "title": "FKTN, 3-KB INS, SVA RETROTRANSPOSON INS_CARDIOMYOPATHY, DILATED, 1X", "submitter_date": "2018-11-19"}, "clinvar_accession": {"acc": "SCV000023510", "version": 4, "type": "SCV", "date_updated": "2018-12-15", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to included disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2009-11-01"}], "external_ids": [{"db": "OMIM", "id": "607440.0001", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "Muscular Dystrophy-Dystroglycanopathy (Congenital with Brain and Eye Anomalies), Type A, 4"}}, {"attribute": {"type": "Description", "value": "Kobayashi et al. (1998) found that 87% of mutant alleles causing the autosomal recessive disorder Fukuyama congenital muscular dystrophy (MDDGA4; 253800) carried an insertion of a 3,062-bp transposon, situated in the 3-prime UTR of the FKTN gene."}, "citations": [{"ids": [{"source": "PubMed", "value": "9690476"}]}], "xrefs": [{"db": "OMIM", "id": "253800", "type": "MIM"}]}, {"attribute": {"type": "Description", "value": "Most Japanese patients with the retrotransposal insertion in the FKTN gene share a common founder haplotype. By applying 2 methods for the study of linkage disequilibrium between flanking polymorphic markers and the disease locus, and of its decay over time, Colombo et al. (2000) calculated the age of the insertion mutation to be approximately 102 generations (95% CI: 86-117 g), or slightly less. 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They noted that the sequence motif was characteristic of a class of retroposon referred to as SINE-VNTR-Alu (SVA)."}, "citations": [{"ids": [{"source": "PubMed", "value": "16222679"}]}]}, {"attribute": {"type": "Description", "value": "Watanabe et al. (2005) established a rapid PCR-based diagnostic method using 3 primers simultaneously in order to detect the 3,062-bp retrotransposal insertion. Fifteen founder chromosomes were detected among 2,814 Japanese individuals. Heterozygous carriers were identified in various regions throughout Japan, with a carrier frequency of approximately 1 in 188. The insertion mutation was found in 1 in 935 Korean individuals but not among 203 Mongolians and 766 mainland Chinese, suggesting that FCMD carriers are rare outside of Japan."}, "citations": [{"ids": [{"source": "PubMed", "value": "16222679"}]}]}, {"attribute": {"type": "Description", "value": "Xiong et al. (2009) reported a Chinese boy with FCMD who was compound heterozygous for 2 mutations in the fukutin gene: the common 3-kb retroposon insertion and R47X (607440.0002). Although the boy's parents were born in Henan and Shanxi Provinces and had no known Japanese ancestry, haplotype analysis showed that both mutant alleles were on Japanese-derived haplotypes."}, "citations": [{"ids": [{"source": "PubMed", "value": "19842201"}]}]}, {"attribute": {"type": "Description", "value": "Cardiomyopathy, Dilated, 1X"}}, {"attribute": {"type": "Description", "value": "In 6 Japanese patients from 4 families with dilated cardiomyopathy and mild or no limb-girdle involvement (CMD1X; 611615), Murakami et al. 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Using this method, they screened 18 FCMD patients and found 16 homozygotes and 2 heterozygotes for the insertion. In the general Japanese population, they found that 6 of 676 persons were heterozygous carriers. Furthermore, they found 3 homozygotes for the FCMD founder mutation among 97 patients who had been said to have probable Duchenne muscular dystrophy (310200) or Becker muscular dystrophy (300376) (DMD/BMD) without any mutation in the DMD gene (300377). On the other hand, there were no FCMD homozygotes but 4 heterozygous carriers among 335 patients with DMD mutations."}, "citations": [{"ids": [{"source": "PubMed", "value": "15103718"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "By sequence analysis, Watanabe et al. (2005) characterized the insertion mutation and found that it was enclosed by target-site duplications at both ends. 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Although the boy's parents were born in Henan and Shanxi Provinces and had no known Japanese ancestry, haplotype analysis showed that both mutant alleles were on Japanese-derived haplotypes."}, "citations": [{"ids": [{"source": "PubMed", "value": "19842201"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000003199", "version": 3, "measures": [{"type": "insertion", "names": [{"value": {"type": "Preferred", "value": "NM_006731.2(FKTN):c.*4392_*4393ins[AB185332.1]"}}, {"value": {"type": "Alternate", "value": "NM_006731.2:c.*4392_*4393insSVA"}}], "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_434t2:c.*4392_*4393ins[AB185332.1]"}, {"type": "HGVS, coding, RefSeq", "value": "NM_006731.2:c.*4392_*4393ins[AB185332.1]"}, {"type": "HGVS, protein"}, {"type": "nucleotide change", "value": "3-KB INS, SVA RETROTRANSPOSON INS"}], "cytogenic_locations": ["9q31"], "measure_relationship": [{"type": "asserted, but not computed", "names": [{"value": {"type": "Preferred", "value": "fukutin"}}], "symbols": [{"value": {"type": "Preferred", "value": "FKTN"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "9", "accession": "NC_000009.12", "start": 105558130, "stop": 105641118, "display_start": 105558130, "display_stop": 105641118, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "9", "accession": "NC_000009.11", "start": 108320410, "stop": 108403398, "display_start": 108320410, "display_stop": 108403398, "strand": "+", "variant_length": 82989, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "2218"}, {"db": "OMIM", "id": "607440", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:3622"}]}], "xrefs": [{"db": "Genetic Testing Registry (GTR)", "id": "GTR000325670"}, {"db": "OMIM", "id": "607440.0001", "type": "Allelic variant"}], "comments": [{"text": "Insertion of retrotransposal insertion sequence into 3'-UTR of FKTN.", "type": "public", "datasource": "NCBI curation"}], "id": 18238}], "names": [{"value": {"type": "Preferred", "value": "NM_006731.2(FKTN):c.*4392_*4393ins[AB185332.1]"}}, {"value": {"type": "Preferred", "value": "NM_006731.2(FKTN):c.*4392_*4393ins[AB185332.1]"}}], "id": 3199}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0009678"}]}, {"value": {"type": "Alternate", "value": "Fukuyama type muscular dystrophy"}}, {"value": {"type": "Alternate", "value": "Muscular dystrophy, congenital progressive, with mental retardation"}}, {"value": {"type": "Alternate", "value": "Muscular dystrophy, congenital, with central nervous system involvement"}}, {"value": {"type": "Alternate", "value": "Cerebromuscular dystrophy, Fukuyama type"}}, {"value": {"type": "Alternate", "value": "Fukuyama congenital muscular dystrophy"}, "xrefs": [{"db": "Genetic Alliance", "id": "Fukuyama+Type+Muscular+Dystrophy/2962"}, {"db": "SNOMED CT", "id": "111502003"}]}, {"value": {"type": "Alternate", "value": "WALKER-WARBURG SYNDROME OR MUSCLE-EYE-BRAIN DISEASE, FKTN-RELATED"}, "xrefs": [{"db": "OMIM", "id": "253800", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A4"}}, {"value": {"type": "Alternate", "value": "Walker-Warburg Syndrome, Fktn-Related"}}], "symbols": [{"value": {"type": "Alternate", "value": "FCMD"}, "xrefs": [{"db": "OMIM", "id": "253800", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "MDDGA4"}, "xrefs": [{"db": "OMIM", "id": "253800", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and CNS migration disturbances that result in changes consistent with cobblestone lissencephaly with cerebral and cerebellar cortical dysplasia. Mild, typical, and severe phenotypes are recognized. Onset typically occurs in early infancy with poor suck, weak cry, and floppiness. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later features include myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech delays, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement after age ten years. 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(2003) identified heterozygosity for a frameshift mutation in the MC4R gene, 112insA, which resulted in complete loss of activity of the protein."}, "citations": [{"ids": [{"source": "PubMed", "value": "12646665"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000014325", "version": 2, "measures": [{"type": "insertion", "names": [{"value": {"type": "Preferred", "value": "MC4R, 1-BP INS, 112A"}}], "attributes": [{"type": "nucleotide change", "value": "1-BP INS, 112A"}], "cytogenic_locations": ["18q22"], "measure_relationship": [{"type": "asserted, but not computed", "names": [{"value": {"type": "Preferred", "value": "melanocortin 4 receptor"}}], "symbols": [{"value": {"type": "Preferred", "value": "MC4R"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "18", "accession": "NC_000018.10", "start": 60371062, "stop": 60372775, "display_start": 60371062, "display_stop": 60372775, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "18", "accession": "NC_000018.9", "start": 58038563, "stop": 58040000, "display_start": 58038563, "display_stop": 58040000, "strand": "-", "variant_length": 1438, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "4160"}, {"db": "OMIM", "id": "155541", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:6932"}]}], "xrefs": [{"db": "OMIM", "id": "155541.0010", "type": "Allelic variant"}], "comments": [{"text": "NCBI staff could not provide an HGVS expression for allelic variant 155541.0010. The location of \"Insertion of A at codon 112 was not specified\".", "type": "public", "datasource": "NCBI curation"}], "id": 29364}], "names": [{"value": {"type": "Preferred", "value": "MC4R, 1-BP INS, 112A"}}], "id": 14325}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20"}, "xrefs": [{"db": "OMIM", "id": "618406", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "MELANOCORTIN 4 RECEPTOR DEFICIENCY"}, "xrefs": [{"db": "OMIM", "id": "618406", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "MC4R DEFICIENCY"}, "xrefs": [{"db": "OMIM", "id": "618406", "type": "MIM"}]}], "symbols": [{"value": {"type": "Preferred", "value": "BMIQ20"}, "xrefs": [{"db": "OMIM", "id": "618406", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "OBESITY"}, "xrefs": [{"db": "OMIM", "id": "618406", "type": "MIM"}]}], "xrefs": [{"db": "MedGen", "id": "C4759928"}, {"db": "OMIM", "id": "618406", "type": "MIM"}]}], "id": 47150}, "date_created": "2013-04-04", "date_last_updated": "2022-08-15", "id": 72904}, "record_status": "current", "title": "MC4R, 1-BP INS, 112A AND BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20", "clinvar_assertions": [{"id": 35662, "submission_id": {"local_key": "155541.0010_OBESITY (BMIQ20)", "submitter": "OMIM", "title": "MC4R, 1-BP INS, 112A_OBESITY (BMIQ20)", "submitter_date": "2019-05-02"}, "clinvar_accession": {"acc": "SCV000035662", "version": 2, "type": "SCV", "date_updated": "2019-05-06", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2003-03-20"}], "external_ids": [{"db": "OMIM", "id": "155541.0010", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In a proband and his mother and sister, all with early-onset obesity (BMIQ20; 618406), Farooqi et al. (2003) identified heterozygosity for a frameshift mutation in the MC4R gene, 112insA, which resulted in complete loss of activity of the protein."}, "citations": [{"ids": [{"source": "PubMed", "value": "12646665"}]}], "xrefs": [{"db": "OMIM", "id": "618406", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "MC4R, 1-BP INS, 112A"}}], "attributes": [{"type": "NonHGVS", "value": "1-BP INS, 112A"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "MC4R"}}]}], "xrefs": [{"db": "OMIM", "id": "155541.0010", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "OBESITY (BMIQ20)"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000076891", "version": 3, "type": "RCV", "date_updated": "2023-01-07", "date_created": "2013-12-19"}, "record_status": "current", "clinical_significance": {"review_status": "reviewed by expert panel", "description": "pathogenic", "date_last_evaluated": "2013-09-05"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["research"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000091372", "version": 2, "measures": [{"type": "insertion", "names": [{"value": {"type": "Preferred", "value": "NM_000535.5(PMS2):c.804-60_804-59insJN866832.1"}}], "attributes": [{"type": "HGVS, non-validated", "value": "NM_000535.5:c.804-60_804-59insJN866832.1"}], "cytogenic_locations": ["7p22.1"], "measure_relationship": [{"type": "asserted, but not computed", "names": [{"value": {"type": "Preferred", "value": "PMS1 homolog 2, mismatch repair system component"}}], "symbols": [{"value": {"type": "Preferred", "value": "PMS2"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "7", "accession": "NC_000007.14", "start": 5970925, "stop": 6009106, "display_start": 5970925, "display_stop": 6009106, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "7", "accession": "NC_000007.13", "start": 6012869, "stop": 6048736, "display_start": 6012869, "display_stop": 6048736, "strand": "-", "variant_length": 35868, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "5395"}, {"db": "OMIM", "id": "600259", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:9122"}], "comments": [{"text": "This gene is cited in the ACMG recommendations of 2013 (PubMed 23788249) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2016 (PubMed 27854360) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2021 (SF v3.0; PubMed 34012068) for reporting secondary findings in clinical exome and genome sequencing.", "type": "public", "datasource": "ClinVar"}, {"text": "This gene is cited in the ACMG recommendations of 2022 (SF v3.1; PubMed 35802134) for reporting secondary findings in clinical exome and genome sequencing.", "type": "public", "datasource": "ClinVar"}]}], "comments": [{"text": "Insertion of retrotransposon SVA_F into intron 7 of PMS2.", "type": "public", "datasource": "NCBI curation"}], "id": 96847}], "names": [{"value": {"type": "Preferred", "value": "NM_000535.5(PMS2):c.804-60_804-59insJN866832.1"}}], "id": 91372}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Lynch syndrome"}, "xrefs": [{"db": "GeneTests", "id": "2622"}, {"db": "Genetic Alliance", "id": "Hereditary+Non-Polyposis+Colorectal+Cancer+%28HNPCC%29/3371"}, {"db": "MONDO", "id": "MONDO:0005835"}]}], "attributes": [{"value": {"type": "public definition", "value": "Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate. 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{"type": "Preferred", "value": "NM_138576.4(BCL11B):c.1262_1267dup (p.Pro422_Pro423insGlnPro)"}}], "attributes": [{"type": "SubmitterVariantId", "value": "GDX:5353460"}], "id": 1695731}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "not provided"}, "xrefs": [{"db": "Developmental Genetics Unit, King Faisal Specialist Hospital & Research Centre", "id": "13DG0619"}]}, {"value": {"type": "Alternate", "value": "none provided"}}], "attributes": [{"value": {"type": "public definition", "value": "The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 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In-frame Insertion of 2 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge"}], "date_last_evaluated": "2022-01-11"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "GeneDx Variant Classification Process June 2021"}, "citations": [{"url": "https://submit.ncbi.nlm.nih.gov/ft/byid/fc81e176/genedx_variant_classification_process_june_2021.pdf"}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "duplication", "attributes": [{"type": "HGVS", "value": "NM_138576.3:c.1262_1267dup"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "BCL11B"}}]}]}], "attributes": [{"type": "SubmitterVariantId", "value": "GDX:5353460"}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "Not Provided"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000076770", "version": 3, "type": "RCV", "date_updated": "2023-03-26", "date_created": "2013-12-19"}, "record_status": "current", "clinical_significance": {"review_status": "reviewed by expert panel", "description": "pathogenic", "date_last_evaluated": "2013-09-05"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["research"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000091265", "version": 2, "measures": [{"type": "insertion", "names": [{"value": {"type": "Preferred", "value": "NM_000251.1(MSH2):c.972_973insNM_002133.2:c.737-1292_737-1109"}}], "attributes": [{"type": "HGVS, non-validated", "value": "NM_000251.1:c.972_973insNM_002133.2:c.737-1292_737-1109"}], "cytogenic_locations": ["2p21-16.3"], "measure_relationship": [{"type": "asserted, but not computed", "names": [{"value": {"type": "Preferred", "value": "mutS homolog 2"}}], "symbols": [{"value": {"type": "Preferred", "value": "MSH2"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 47403067, "stop": 47709830, "display_start": 47403067, "display_stop": 47709830, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 47630205, "stop": 47710366, "display_start": 47630205, "display_stop": 47710366, "strand": "+", "variant_length": 80162, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "4436"}, {"db": "OMIM", "id": "609309", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:7325"}], "comments": [{"text": "This gene is cited in the ACMG recommendations of 2013 (PubMed 23788249) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2016 (PubMed 27854360) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2021 (SF v3.0; 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"names": [{"value": {"type": "Preferred", "value": "Hereditary factor IX deficiency disease"}, "xrefs": [{"db": "Genetic Alliance", "id": "Hemophilia+B/3315"}, {"db": "SNOMED CT", "id": "41788008"}]}, {"value": {"type": "Alternate", "value": "F9 DEFICIENCY"}, "xrefs": [{"db": "OMIM", "id": "306900", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "PLASMA THROMBOPLASTIN COMPONENT DEFICIENCY"}, "xrefs": [{"db": "OMIM", "id": "306900", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Hemophilia B"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0010604"}]}, {"value": {"type": "Alternate", "value": "Christmas disease"}}, {"value": {"type": "Alternate", "value": "Factor IX deficiency"}}, {"value": {"type": "Alternate", "value": "HEM B"}}], "symbols": [{"value": {"type": "Preferred", "value": "HEMB"}, "xrefs": [{"db": "OMIM", "id": "306900", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "Hemophilia B is characterized by deficiency in factor 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The age of diagnosis and frequency of bleeding episodes are related to the level of factor IX clotting activity. In individuals with severe hemophilia B, spontaneous joint or deep-muscle bleeding is the most frequent sign. Individuals with severe hemophilia B are usually diagnosed during the first two years of life; without prophylactic treatment, they may average up to two to five spontaneous bleeding episodes each month. Individuals with moderate hemophilia B seldom have spontaneous bleeding; however, they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years; the frequency of bleeding episodes varies from once a month to once a year. Individuals with mild hemophilia B do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions; the frequency of bleeding may vary from once a year to once every ten years. Individuals with mild hemophilia B are often not diagnosed until later in life. In any individual with hemophilia B, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. Approximately 30% of heterozygous females have factor IX clotting activity lower than 40% and are at risk for bleeding (even if the affected family member has mild hemophilia B), although symptoms are usually mild. After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1495"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "8732"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301668"}, {"source": "BookShelf", "value": "NBK1495"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "PubMed", "value": "22274582"}], "type": "Translational/Evidence-based", "abbrev": "EuroGenetest, 2012"}, {"ids": [{"source": "PubMed", "value": "23157203"}], "type": "practice guideline", "abbrev": "UKHCDO, 2013"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0010604"}, {"db": "MeSH", "id": "D002836"}, {"db": "MedGen", "id": "C0008533"}, {"db": "Orphanet", "id": "98879"}, {"db": "OMIM", "id": "306900", "type": "MIM"}]}], "id": 2993}, "date_created": "2019-09-29", "date_last_updated": "2022-04-23", "id": 1950334}, "record_status": "current", "title": "Single allele AND Hereditary factor IX deficiency disease", "clinvar_assertions": [{"id": 1769984, "submission_id": {"local_key": "154156796_306900", "submitter": "NIHR Bioresource Rare Diseases, University of Cambridge", "submitted_assembly": "GRCh37", "submitter_date": "2019-03-28"}, "clinvar_accession": {"acc": "SCV000900011", "version": 1, "type": "SCV", "date_updated": "2019-09-29", "date_created": "2019-09-29", "org_id": "505998", "org_type": "primary", "org_category": "consortium"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["likely pathogenic"], "citations": [{"ids": [{"source": "PubMed", "value": "31064749"}], "type": "general"}], "date_last_evaluated": "2019-02-01"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "ACMG Guidelines, 2015"}, "citations": [{"ids": [{"source": "PubMed", "value": "25741868"}]}]}], "observed_in": [{"sample": {"origin": "unknown", "ethnicity": "European", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "number_tested": 1, "gender": "male"}, "methods": ["research"], "observed_data": [{"attribute": {"type": "Hemizygote", "integer_value": 1}}, {"attribute": {"type": "SampleLocalID", "value": "TGP0454"}}]}], "measures": {"type": "Variant", "measures": [{"type": "complex", "sequence_locations": [{"assembly": "GRCh37", "chr": "X", "start": 154156796, "stop": 154227925, "variant_length": 71130}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "F8"}}]}]}], "comments": [{"text": "Deletion of intron 1 to intron 6 ; Inversion of intron 6 to intron 13; Deletion X:154,145,074 - 154,171,298 - intron 13 to intron 14"}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "OMIM", "id": "306900", "type": "MIM"}]}]}, "citations": [{"ids": [{"source": "PubMed", "value": "31064749"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": "31064749"}], "type": "general"}], "study_name": "ThromboGenomics"}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV001580364", "version": 1, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2021-08-27"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "likely pathogenic"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}]}], "measures": {"type": "Variant", "acc": "VCV001210283", "version": 1, "measures": [{"type": "complex", "names": [{"value": {"type": "Preferred", "value": "NC_000023.11:g.[124350560_124365777del;124365777_124365917inv;124365911_124365916del]"}}], "attributes": [{"type": "HGVS, genomic, top level", "value": "NC_000023.11:g.[124350560_124365777del;124365777_124365917inv;124365911_124365916del]", "integer_value": 38}], "measure_relationship": [{"type": "asserted, but not computed", "names": [{"value": {"type": "Preferred", "value": "SH2 domain containing 1A"}}], "symbols": [{"value": {"type": "Preferred", "value": "SH2D1A"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "X", "accession": "NC_000023.11", "start": 124346563, "stop": 124373160, "display_start": 124346563, "display_stop": 124373160, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "X", "accession": "NC_000023.10", "start": 123480131, "stop": 123507009, "display_start": 123480131, "display_stop": 123507009, "strand": "+", "variant_length": 26879, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "4068"}, {"db": "OMIM", "id": "300490", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:10820"}]}], "id": 1200283}], "names": [{"value": {"type": "Preferred", "value": "NC_000023.11:g.[124350560_124365777del;124365777_124365917inv;124365911_124365916del]"}}], "id": 1210283}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "X-linked lymphoproliferative disease due to SH2D1A deficiency"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0024551"}]}, {"value": {"type": "Alternate", "value": "IMMUNODEFICIENCY 5"}, "xrefs": [{"db": "OMIM", "id": "308240", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "IMMUNODEFICIENCY, X-LINKED PROGRESSIVE COMBINED VARIABLE"}, "xrefs": [{"db": "OMIM", "id": "308240", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "INFECTIOUS MONONUCLEOSIS, SEVERE, SUSCEPTIBILITY TO"}, "xrefs": [{"db": "OMIM", "id": "308240", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Lymphoproliferative syndrome 1, X-linked"}, "xrefs": [{"db": "Genetic Alliance", "id": "Lymphoproliferative+syndrome+X-linked+1/4379"}]}, {"value": {"type": "Alternate", "value": "Purtilo syndrome"}}, {"value": {"type": "Alternate", "value": "EBV infection severe susceptibility to"}}, {"value": {"type": "Alternate", "value": "Epstein Barr virus infection familial fatal"}}, {"value": {"type": "Alternate", "value": "Duncan's syndrome"}}, {"value": {"type": "Alternate", "value": "Duncan disease"}}], "symbols": [{"value": {"type": "Alternate", "value": "LYP"}, "xrefs": [{"db": "OMIM", "id": "308240", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "XLP"}, "xrefs": [{"db": "OMIM", "id": "308240", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "EBVS"}, "xrefs": [{"db": "OMIM", "id": "308240", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "IMD5"}, "xrefs": [{"db": "OMIM", "id": "308240", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "XLP1"}, "xrefs": [{"db": "OMIM", "id": "308240", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "XLPD"}, "xrefs": [{"db": "OMIM", "id": "308240", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "X-linked lymphoproliferative disease (XLP) has two recognizable subtypes, XLP1 and XLP2. XLP1 is characterized predominantly by one of three commonly recognized phenotypes: Inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis. Dysgammaglobulinemia. Lymphoproliferative disease (malignant lymphoma). XLP2 is most often characterized by HLH (often associated with EBV), dysgammaglobulinemia, and inflammatory bowel disease. HLH resulting from EBV infection is associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages. Dysgammaglobulinemia is typically hypogammaglobulinemia of one or more immunoglobulin subclasses. The malignant lymphomas are typically B-cell lymphomas, non-Hodgkin type, often extranodal, and in particular involving the intestine."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1406"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "7906"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301580"}, {"source": "BookShelf", "value": "NBK1406"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0024551"}, {"db": "MedGen", "id": "C5399825"}, {"db": "Orphanet", "id": "2442"}, {"db": "OMIM", "id": "308240", "type": "MIM"}]}], "id": 3039}, "date_created": "2021-08-27", "date_last_updated": "2022-04-23", "id": 3551069}, "record_status": "current", "title": "NC_000023.11:g.[124350560_124365777del;124365777_124365917inv;124365911_124365916del] AND X-linked lymphoproliferative disease due to SH2D1A deficiency", "clinvar_assertions": [{"id": 3550971, "submission_id": {"local_key": "SUB10199849", "submitter": "Department of Neurology, Hunan Children's Hospital", "title": "SUB10199849", "submitted_assembly": "GRCh38", "submitter_date": "2021-08-25"}, "clinvar_accession": {"acc": "SCV001786702", "version": 1, "type": "SCV", "date_updated": "2021-08-27", "date_created": "2021-08-27", "org_id": "508218", "org_type": "primary", "org_category": "clinic"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["likely pathogenic"], "comments": [{"text": "We use extended WES to identify a novel genomic structure variation combined by paracentric inversion and large size deletions of the SH2D1A gene in an XLP1 male patient. The variant functionally disrupted the splice site causing the exon 2 skipping was confirmed by Inversion-PCR, RT-PCR, and Gap-PCR."}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "gender": "male"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Hemizygote", "integer_value": 1}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NC_000023.11:g.[124350560_124365777del;124365777_124365917inv;124365911_124365916del]"}], "measure_relationship": [{"type": "variant in gene", "names": [{"value": {"type": "Preferred", "value": "SH2 domain containing 1A"}}], "symbols": [{"value": {"type": "Preferred", "value": "SH2D1A"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "OMIM", "id": "308240"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000626017", "version": 2, "type": "RCV", 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"sequence_locations": [{"assembly": "GRCh38", "chr": "5", "accession": "NC_000005.10", "start": 38923237, "stop": 38923237, "display_start": 38923237, "display_stop": 38923237, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 38923237, "reference_allele_vcf": "G", "alternate_allele_vcf": "C"}, {"assembly": "GRCh37", "chr": "5", "accession": "NC_000005.9", "start": 38923339, "stop": 38923339, "display_start": 38923339, "display_stop": 38923339, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 38923339, "reference_allele_vcf": "G", "alternate_allele_vcf": "C"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "oncostatin M receptor"}}], "symbols": [{"value": {"type": "Preferred", "value": "OSMR"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "5", "accession": "NC_000005.10", "start": 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[{"value": {"type": "Preferred", "value": "Amyloidosis, primary localized cutaneous, 1"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0024522"}]}, {"value": {"type": "Alternate", "value": "Lichen amyloidosis familial"}}, {"value": {"type": "Alternate", "value": "Amyloidosis 9"}}, {"value": {"type": "Alternate", "value": "Amyloidosis IX"}}, {"value": {"type": "Alternate", "value": "AMYLOIDOSIS, PRIMARY CUTANEOUS, 1"}, "xrefs": [{"db": "OMIM", "id": "105250", "type": "MIM"}]}], "symbols": [{"value": {"type": "Alternate", "value": "PCA1"}, "xrefs": [{"db": "OMIM", "id": "105250", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "PLCA1"}, "xrefs": [{"db": "OMIM", "id": "105250", "type": "MIM"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0024522"}, {"db": "MedGen", "id": "C4551501"}, {"db": "Orphanet", "id": "353220"}, {"db": "OMIM", "id": "105250", "type": "MIM"}]}], "id": 2117}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 65755}, "record_status": "current", "title": "NM_003999.3(OSMR):c.1853G>C (p.Gly618Ala) AND Amyloidosis, primary localized cutaneous, 1", "clinvar_assertions": [{"id": 28459, "submission_id": {"local_key": "601743.0002_AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1", "submitter": "OMIM", "title": "OSMR, GLY618ALA_AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1", "submitter_date": "2017-03-07"}, "clinvar_accession": {"acc": "SCV000028459", "version": 2, "type": "SCV", "date_updated": "2017-03-10", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2008-01-01"}], "external_ids": [{"db": "OMIM", "id": "601743.0002", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature 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(2008) found an 1853G-C transversion in the OSMR gene that resulted in a gly618-to-ala substitution (G618A). Microsatellite analysis around the OSMR gene indicated that the 2 families probably shared a common British ancestry."}, "citations": [{"ids": [{"source": "PubMed", "value": "18179886"}]}], "xrefs": [{"db": "OMIM", "id": "105250", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "OSMR, GLY618ALA"}}], "attributes": [{"type": "NonHGVS", "value": "GLY618ALA"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "OSMR"}}]}], "xrefs": [{"db": "OMIM", "id": "601743.0002", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000022887", "version": 4, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2011-12-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In 34 individuals with Leri-Weill dyschondrosteosis (127300) and 4 with Langer mesomelic dysplasia (249700) from 12 Spanish multiplex families, 2 of which had previously been studied (Sabherwal et al., 2004, 2004), Barca-Tierno et al. 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However, chondrocytes were enlarged and in pairs in the reserve zone of the LMD growth plate, and their columnar stacking in the proliferative zone was disorganized, with the chondrocytes appearing in less-defined columns and in smaller clusters."}, "citations": [{"ids": [{"source": "PubMed", "value": "21712857"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000029994", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_000451.4(SHOX):c.508G>C (p.Ala170Pro)"}}], "canonical_spdi": "NC_000024.10:640841:G:C", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_710t1:c.508G>C"}, {"type": "HGVS, coding, LRG", "value": "LRG_710t2:c.508G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000451.4:c.508G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_006883.2:c.508G>C"}, {"type": "HGVS, genomic, LRG", "value": "LRG_710:g.21499G>C"}, {"type": "HGVS, genomic, RefSeqGene", "value": 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"SO:0001583"}, {"db": "RefSeq", "id": "NM_006883.2:c.508G>C"}]}, {"type": "ProteinChange1LetterCode", "value": "A170P"}, {"type": "ProteinChange3LetterCode", "value": "ALA170PRO"}], "cytogenic_locations": ["Xp22.33", "Yp11.2"], "sequence_locations": [{"assembly": "GRCh38", "chr": "X", "accession": "NC_000023.11", "start": 640842, "stop": 640842, "display_start": 640842, "display_stop": 640842, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 640842, "reference_allele_vcf": "G", "alternate_allele_vcf": "C"}, {"assembly": "GRCh38", "chr": "Y", "accession": "NC_000024.10", "start": 640842, "stop": 640842, "display_start": 640842, "display_stop": 640842, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 640842, "reference_allele_vcf": "G", "alternate_allele_vcf": "C"}, {"assembly": "GRCh37", "chr": "X", "accession": "NC_000023.10", "start": 601577, "stop": 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"GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh38", "chr": "Y", "accession": "NC_000024.10", "start": 624344, "stop": 659411, "display_start": 624344, "display_stop": 659411, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}], "xrefs": [{"db": "Gene", "id": "6473"}, {"db": "OMIM", "id": "312865", "type": "MIM"}, {"db": "OMIM", "id": "400020", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:10853"}]}], "xrefs": [{"db": "OMIM", "id": "312865.0014", "type": "Allelic variant"}, {"db": "dbSNP", "id": "397514461", "type": "rs"}], "id": 38949}], "names": [{"value": {"type": "Preferred", "value": "NM_000451.4(SHOX):c.508G>C (p.Ala170Pro)"}}, {"value": {"type": "Preferred", "value": "NM_000451.4(SHOX):c.508G>C (p.Ala170Pro)"}}], "xrefs": [{"db": "ClinGen", "id": "CA128821"}], "id": 29994}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Leri-Weill dyschondrosteosis"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0007481"}]}, {"value": {"type": "Alternate", "value": "Dyschondrosteosis"}}, {"value": {"type": "Alternate", "value": "L\u00e9ri-Weill dyschondrosteosis"}}], "symbols": [{"value": {"type": "Preferred", "value": "LWD"}, "xrefs": [{"db": "OMIM", "id": "127300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "DCO"}, "xrefs": [{"db": "OMIM", "id": "127300", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the short stature homeobox-containing gene (SHOX), ranges from Leri-Weill dyschondrosteosis (LWD) at the severe end of the spectrum to nonspecific short stature at the mild end of the spectrum. In adults with SHOX deficiency, the proportion of LWD versus short stature without features of LWD is not well defined. In LWD the classic clinical triad is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shortened in relation to the proximal portion, can be evident first in school-aged children and increases with age in frequency and severity. Madelung deformity (abnormal alignment of the radius, ulna, and carpal bones at the wrist) typically develops in mid-to-late childhood and is more common and severe in females. The phenotype of short stature caused by SHOX deficiency in the absence of mesomelia and Madelung deformity (called SHOX-deficient short stature in this GeneReview) is highly variable, even within the same family."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1215"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "3224"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301394"}, {"source": "BookShelf", "value": "NBK1215"}], "type": "review", "abbrev": "GeneReviews"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0007481"}, {"db": "MedGen", "id": "C0265309"}, {"db": "OMIM", "id": "127300", "type": "MIM"}]}], "id": 2777}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 80390}, "record_status": "current", "title": "NM_000451.4(SHOX):c.508G>C (p.Ala170Pro) AND Leri-Weill dyschondrosteosis", "clinvar_assertions": [{"id": 49434, "submission_id": {"local_key": "312865.0014_LERI-WEILL DYSCHONDROSTEOSIS", "submitter": "OMIM", "title": "SHOX, ALA170PRO_LERI-WEILL DYSCHONDROSTEOSIS", "submitter_date": "2018-11-07"}, "clinvar_accession": {"acc": "SCV000044178", "version": 3, "type": "SCV", "date_updated": "2018-11-09", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2011-12-01"}], "external_ids": [{"db": "OMIM", "id": "312865.0014", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In 34 individuals with Leri-Weill dyschondrosteosis (127300) and 4 with Langer mesomelic dysplasia (249700) from 12 Spanish multiplex families, 2 of which had previously been studied (Sabherwal et al., 2004, 2004), Barca-Tierno et al. (2011) identified heterozygosity or homozygosity, respectively, for a 508G-C transversion in the SHOX gene, resulting in an ala170-to-pro (A170P) substitution. Microsatellite analysis revealed a shared haplotype around SHOX, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the 12 families were of that ethnic group. The mutation was not found in 359 Eastern European Gypsies. Transient transfection studies in U2OS cells demonstrated that the A170P mutant protein failed to localize to the nucleus. Expression of mutant SHOX in the human growth plate of a 22-week-old fetus homozygous for A170P was compared to that of a 23-week-old normal fetal growth plate: SHOX was observed in the resting, proliferative, and hypertrophic zones of both the control and the LMD growth plate. However, chondrocytes were enlarged and in pairs in the reserve zone of the LMD growth plate, and their columnar stacking in the proliferative zone was disorganized, with the chondrocytes appearing in less-defined columns and in smaller clusters."}, "citations": [{"ids": [{"source": "PubMed", "value": "21712857"}]}], "xrefs": [{"db": "OMIM", "id": "127300", "type": "MIM"}, {"db": "OMIM", "id": "249700", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "SHOX, ALA170PRO"}}], "attributes": [{"type": "NonHGVS", "value": "ALA170PRO"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "SHOX"}}]}], "xrefs": [{"db": "OMIM", "id": "312865.0014", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "LERI-WEILL DYSCHONDROSTEOSIS"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000022888", "version": 4, "type": "RCV", "date_updated": "2022-04-23", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2011-12-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In 34 individuals with Leri-Weill dyschondrosteosis (127300) and 4 with Langer mesomelic dysplasia (249700) from 12 Spanish multiplex families, 2 of which had previously been studied (Sabherwal et al., 2004, 2004), Barca-Tierno et al. 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However, chondrocytes were enlarged and in pairs in the reserve zone of the LMD growth plate, and their columnar stacking in the proliferative zone was disorganized, with the chondrocytes appearing in less-defined columns and in smaller clusters."}, "citations": [{"ids": [{"source": "PubMed", "value": "21712857"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000029994", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_000451.4(SHOX):c.508G>C (p.Ala170Pro)"}}], "canonical_spdi": "NC_000024.10:640841:G:C", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_710t1:c.508G>C"}, {"type": "HGVS, coding, LRG", "value": "LRG_710t2:c.508G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000451.4:c.508G>C"}, {"type": "HGVS, coding, RefSeq", "value": "NM_006883.2:c.508G>C"}, {"type": "HGVS, genomic, LRG", "value": "LRG_710:g.21499G>C"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_009385.2:g.21499G>C"}, {"type": "HGVS, genomic, top level", "value": "NC_000023.11:g.640842G>C", "integer_value": 38}, {"type": "HGVS, genomic, top level", "value": "NC_000024.10:g.640842G>C", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000024.9:g.551577G>C", "integer_value": 37}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000023.10:g.601577G>C", "integer_value": 37}, {"type": "HGVS, protein"}, {"type": "HGVS, protein", "value": "LRG_710p1:p.Ala170Pro"}, {"type": "HGVS, protein", "value": "LRG_710p2:p.Ala170Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_000442.1:p.Ala170Pro"}, {"type": "HGVS, protein, RefSeq", "value": "NP_006874.1:p.Ala170Pro"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_000451.4:c.508G>C"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_006883.2:c.508G>C"}]}, {"type": "ProteinChange1LetterCode", "value": "A170P"}, {"type": "ProteinChange3LetterCode", "value": "ALA170PRO"}], "cytogenic_locations": ["Xp22.33", "Yp11.2"], "sequence_locations": [{"assembly": "GRCh38", "chr": "X", "accession": "NC_000023.11", "start": 640842, "stop": 640842, "display_start": 640842, "display_stop": 640842, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 640842, "reference_allele_vcf": "G", "alternate_allele_vcf": "C"}, {"assembly": "GRCh38", "chr": "Y", "accession": "NC_000024.10", "start": 640842, "stop": 640842, "display_start": 640842, "display_stop": 640842, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 640842, "reference_allele_vcf": "G", "alternate_allele_vcf": "C"}, {"assembly": "GRCh37", "chr": "X", "accession": "NC_000023.10", "start": 601577, "stop": 601577, "display_start": 601577, "display_stop": 601577, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 601577, "reference_allele_vcf": "G", "alternate_allele_vcf": "C"}, {"assembly": "GRCh37", "chr": "Y", "accession": "NC_000024.9", "start": 551577, "stop": 551577, "display_start": 551577, "display_stop": 551577, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 551577, "reference_allele_vcf": "G", "alternate_allele_vcf": "C"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "short stature homeobox"}}], "symbols": [{"value": {"type": "Preferred", "value": "SHOX"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "X", "accession": "NC_000023.11", "start": 624344, "stop": 659411, "display_start": 624344, "display_stop": 659411, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh38", "chr": "Y", "accession": "NC_000024.10", "start": 624344, "stop": 659411, "display_start": 624344, "display_stop": 659411, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}], "xrefs": [{"db": "Gene", "id": "6473"}, {"db": "OMIM", "id": "312865", "type": "MIM"}, {"db": "OMIM", "id": "400020", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:10853"}]}], "xrefs": [{"db": "OMIM", "id": "312865.0014", "type": "Allelic variant"}, {"db": "dbSNP", "id": "397514461", "type": "rs"}], "id": 38949}], "names": [{"value": {"type": "Preferred", "value": "NM_000451.4(SHOX):c.508G>C (p.Ala170Pro)"}}, {"value": {"type": "Preferred", "value": "NM_000451.4(SHOX):c.508G>C (p.Ala170Pro)"}}], "xrefs": [{"db": "ClinGen", "id": "CA128821"}], "id": 29994}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Langer mesomelic dysplasia syndrome"}, "xrefs": [{"db": "Genetic Alliance", "id": "Langer+mesomelic+dysplasia/4083"}, {"db": "SNOMED CT", "id": "38494008"}]}, {"value": {"type": "Alternate", "value": "Langer mesomelic dysplasia"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0009588"}]}, {"value": {"type": "Alternate", "value": "Dyschondrosteosis, homozygous"}}, {"value": {"type": "Alternate", "value": "Mesomelic dwarfism of the hypoplastic ulna, fibula and mandible type"}}], "symbols": [{"value": {"type": "Preferred", "value": "LMD"}, "xrefs": [{"db": "OMIM", "id": "249700", "type": "MIM"}]}], "attributes": [{"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "3553"}]}], "xrefs": [{"db": "MONDO", "id": "MONDO:0009588"}, {"db": "MedGen", "id": "C0432230"}, {"db": "Orphanet", "id": "2632"}, {"db": "OMIM", "id": "249700", "type": "MIM"}]}], "id": 2778}, "date_created": "2013-04-04", "date_last_updated": "2022-04-23", "id": 80391}, "record_status": "current", "title": "NM_000451.4(SHOX):c.508G>C (p.Ala170Pro) AND Langer mesomelic dysplasia syndrome", "clinvar_assertions": [{"id": 49435, "submission_id": {"local_key": "312865.0014_LANGER MESOMELIC DYSPLASIA", "submitter": "OMIM", "title": "SHOX, ALA170PRO_LANGER MESOMELIC DYSPLASIA", "submitter_date": "2018-11-07"}, "clinvar_accession": {"acc": "SCV000044179", "version": 3, "type": "SCV", "date_updated": "2018-11-09", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to included disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2011-12-01"}], "external_ids": [{"db": "OMIM", "id": "312865.0014", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In 34 individuals with Leri-Weill dyschondrosteosis (127300) and 4 with Langer mesomelic dysplasia (249700) from 12 Spanish multiplex families, 2 of which had previously been studied (Sabherwal et al., 2004, 2004), Barca-Tierno et al. (2011) identified heterozygosity or homozygosity, respectively, for a 508G-C transversion in the SHOX gene, resulting in an ala170-to-pro (A170P) substitution. Microsatellite analysis revealed a shared haplotype around SHOX, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the 12 families were of that ethnic group. The mutation was not found in 359 Eastern European Gypsies. Transient transfection studies in U2OS cells demonstrated that the A170P mutant protein failed to localize to the nucleus. Expression of mutant SHOX in the human growth plate of a 22-week-old fetus homozygous for A170P was compared to that of a 23-week-old normal fetal growth plate: SHOX was observed in the resting, proliferative, and hypertrophic zones of both the control and the LMD growth plate. However, chondrocytes were enlarged and in pairs in the reserve zone of the LMD growth plate, and their columnar stacking in the proliferative zone was disorganized, with the chondrocytes appearing in less-defined columns and in smaller clusters."}, "citations": [{"ids": [{"source": "PubMed", "value": "21712857"}]}], "xrefs": [{"db": "OMIM", "id": "127300", "type": "MIM"}, {"db": "OMIM", "id": "249700", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "SHOX, ALA170PRO"}}], "attributes": [{"type": "NonHGVS", "value": "ALA170PRO"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "SHOX"}}]}], "xrefs": [{"db": "OMIM", "id": "312865.0014", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "included", "value": "LANGER MESOMELIC DYSPLASIA"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV001025630", "version": 4, "type": "RCV", "date_updated": "2023-02-07", "date_created": "2020-03-16"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, multiple submitters, no conflicts", "description": "other", "date_last_evaluated": "2020-07-22"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown", "number_tested": 1}, "methods": ["clinical testing", "clinical testing"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}, {"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000090317", "version": 11, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_000249.4(MLH1):c.677+5G>A"}}], "canonical_spdi": "NC_000003.12:37012103:G:A", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_216t1:c.677+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354621.2:c.-140+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354624.2:c.-150+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354625.2:c.-150+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354626.2:c.-150+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354627.2:c.-150+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354622.2:c.-253+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354623.2:c.-253+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001167618.3:c.-47+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001167619.3:c.-47+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001258273.2:c.-47+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001258274.3:c.-47+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354615.2:c.-47+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354616.2:c.-47+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354617.2:c.-47+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354618.2:c.-47+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354619.2:c.-47+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001167617.3:c.383+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354620.2:c.383+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354629.2:c.578+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000249.4:c.677+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001258271.2:c.677+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354628.2:c.677+5G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001354630.2:c.677+5G>A"}, {"type": "HGVS, genomic, LRG", "value": "LRG_216:g.23755G>A"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_007109.2:g.23755G>A"}, {"type": "HGVS, genomic, top level", "value": "NC_000003.12:g.37012104G>A", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000003.11:g.37053595G>A", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_000249.3:c.677+5G>A"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein"}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_000249.4:c.677+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001167617.3:c.383+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001167618.3:c.-47+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001167619.3:c.-47+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001258271.2:c.677+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001258273.2:c.-47+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001258274.3:c.-47+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354615.2:c.-47+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354616.2:c.-47+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354617.2:c.-47+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354618.2:c.-47+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354619.2:c.-47+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354620.2:c.383+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354621.2:c.-140+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354622.2:c.-253+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354623.2:c.-253+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354624.2:c.-150+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354625.2:c.-150+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354626.2:c.-150+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354627.2:c.-150+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354628.2:c.677+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354629.2:c.578+5G>A"}]}, {"type": "MolecularConsequence", "value": "intron variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001627"}, {"db": "RefSeq", "id": "NM_001354630.2:c.677+5G>A"}]}], "cytogenic_locations": ["3p22.2"], "sequence_locations": [{"assembly": "GRCh38", "chr": "3", "accession": "NC_000003.12", "start": 37012104, "stop": 37012104, "display_start": 37012104, "display_stop": 37012104, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 37012104, "reference_allele_vcf": "G", "alternate_allele_vcf": "A"}, {"assembly": "GRCh37", "chr": "3", "accession": "NC_000003.11", "start": 37053595, "stop": 37053595, "display_start": 37053595, "display_stop": 37053595, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 37053595, "reference_allele_vcf": "G", "alternate_allele_vcf": "A"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "mutL homolog 1"}}], "symbols": [{"value": {"type": "Preferred", "value": "MLH1"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "3", "accession": "NC_000003.12", "start": 36993466, "stop": 37050846, "display_start": 36993466, "display_stop": 37050846, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "3", "accession": "NC_000003.11", "start": 37034840, "stop": 37092336, "display_start": 37034840, "display_stop": 37092336, "strand": "+", "variant_length": 57497, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "4292"}, {"db": "OMIM", "id": "120436", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:7127"}], "comments": [{"text": "This gene is cited in the ACMG recommendations of 2013 (PubMed 23788249) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2016 (PubMed 27854360) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2021 (SF v3.0; PubMed 34012068) for reporting secondary findings in clinical exome and genome sequencing.", "type": "public", "datasource": "ClinVar"}, {"text": "This gene is cited in the ACMG recommendations of 2022 (SF v3.1; PubMed 35802134) for reporting secondary findings in clinical exome and genome sequencing.", "type": "public", "datasource": "ClinVar"}]}], "xrefs": [{"db": "International Society for Gastrointestinal Hereditary Tumours (InSiGHT)", "id": "c.677+5G>A"}, {"db": "Quest Diagnostics Nichols Institute San Juan Capistrano", "id": "2850174"}, {"db": "dbSNP", "id": "587779034", "type": "rs"}], "id": 95791}], "names": [{"value": {"type": "Preferred", "value": "NM_000249.4(MLH1):c.677+5G>A"}}, {"value": {"type": "Preferred", "value": "NM_000249.4(MLH1):c.677+5G>A"}}, {"value": {"type": "Preferred", "value": "NM_000249.4(MLH1):c.677+5G>A"}}], "xrefs": [{"db": "ClinGen", "id": "CA011569"}], "id": 90317}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Hereditary cancer-predisposing syndrome"}, "xrefs": [{"db": "SNOMED CT", "id": "699346009"}]}, {"value": {"type": "Alternate", "value": "Neoplastic Syndromes, Hereditary"}, "xrefs": [{"db": "MeSH", "id": "D009386"}]}, {"value": {"type": "Alternate", "value": "Tumor predisposition"}}, {"value": {"type": "Alternate", "value": "Cancer predisposition"}, "xrefs": [{"db": "Genetic Alliance", "id": "Hereditary+Cancer/3345"}]}, {"value": {"type": "Alternate", "value": "Hereditary Cancer Syndrome"}}], "attributes": [{"value": {"type": "keyword", "value": "Neoplasm"}}, {"value": {"type": "keyword", "value": "Hereditary cancer syndrome"}}], "citations": [{"ids": [{"source": "pmc", "value": "3075918"}], "type": "practice guideline", "abbrev": "IARC, 2008"}, {"ids": [{"source": "PubMed", "value": "25394175"}], "type": "practice guideline", "abbrev": "ACMG/NSGC, 2015"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0015356"}, {"db": "MeSH", "id": "D009386"}, {"db": "MedGen", "id": "C0027672"}]}], "id": 13598}, "date_created": "2020-03-16", "date_last_updated": "2023-02-07", "id": 2345939}, "record_status": "current", "title": "NM_000249.4(MLH1):c.677+5G>A AND Hereditary cancer-predisposing syndrome", "clinvar_assertions": [{"id": 2327848, "submission_id": {"local_key": "a453800", "submitter": "Ambry Genetics", "submitted_assembly": "GRCh37", "submitter_date": "2022-11-11"}, "clinvar_accession": {"acc": "SCV001187858", "version": 3, "type": "SCV", "date_updated": "2022-11-29", "date_created": "2020-03-16", "org_id": "61756", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["pathogenic"], "citations": [{"ids": [{"source": "PubMed", "value": "23354634"}]}, {"ids": [{"source": "PubMed", "value": "24344984"}]}, {"ids": [{"source": "PubMed", "value": "28874130"}]}], "comments": [{"text": "The c.677+5G>A pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 8 in the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was identified and segregated with disease in individuals meeting Amsterdam Criteria II with colorectal tumors demonstrating MSI-H and/or loss of MLH1 protein expression by IHC (Wielandt AM et al. Rev Med Chil, 2012 Sep;140:1132-9; Ambry internal data) and has been reported in individuals of South American decent (Dominguez-Valentin M et al. Hered Cancer Clin Pract 2013 Dec;11:18; Rossi BM et al. BMC Cancer 2017 Sep;17:623). In addition, this variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation."}], "date_last_evaluated": "2019-08-27"}], "external_ids": [{"db": "Ambry Genetics", "id": "a453800"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "Ambry General Variant Classification Scheme_2022"}, "citations": [{"url": "https://submit.ncbi.nlm.nih.gov/ft/byid/5hsvndk6/ambry_general_variant_classification_scheme_2022.pdf"}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown", "number_tested": 1}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_000249.3:c.677+5G>A"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "MLH1"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "MedGen", "id": "C0027672", "type": "CUI"}]}]}}, {"id": 3412416, "submission_id": {"local_key": "Db4KrQBSZeoE7-orUyypkSOa-eMm36ihODQ12xtV7eU|MedGen:C0027672", "submitter": "Color Diagnostics, LLC DBA Color Health", "submitted_assembly": "GRCh37", "submitter_date": "2021-06-11"}, "clinvar_accession": {"acc": "SCV001735153", "version": 1, "type": "SCV", "date_updated": "2021-06-19", "date_created": "2021-06-19", "org_id": "505849", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["likely pathogenic"], "comments": [{"text": "This variant causes a G to A nucleotide substitution at the +5 position of intron 8 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Studies using carrier RNA from blood and minigene assay have shown that this variant causes skipping of exon 8 or skipping of exon 6 and 8 in the RNA transcripts (PMID: 32363481). The aberrant transcripts are expected to create a premature translation stop signal and result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers and to segregate with disease (PMID: 24344984, 28874130, 32363481, 32549215). Microsatellite instability and loss of MLH1 and PMS2 protein expression have been reported in tumor samples from these individuals (PMID: 32363481). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic."}], "date_last_evaluated": "2020-07-22"}], "external_ids": [{"db": "Color Health, Inc", "id": "Db4KrQBSZeoE7-orUyypkSOa-eMm36ihODQ12xtV7eU"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "ACMG Guidelines, 2015"}, "citations": [{"ids": [{"source": "PubMed", "value": "25741868"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_000249.3:c.677+5G>A"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "MLH1"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "MedGen", "id": "C0027672", "type": "CUI"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000014462", "version": 19, "type": "RCV", "date_updated": "2023-03-26", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2002-08-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In affected members of 2 PEOA1 (157640) families originating from a small village in northwest Sicily, Lamantea et al. (2002) identified a heterozygous 2869G-T transversion in the POLG gene, resulting in an ala957-to-ser (A957S) substitution. One patient in 1 of the families was homozygous for the A957S mutation and showed a more severe phenotype with earlier onset and a much higher amount of mtDNA deletions than his mildly affected heterozygous mother. Microsatellite analysis showed a common disease haplotype, supporting a common origin in these 2 families."}, "citations": [{"ids": [{"source": "PubMed", "value": "12210792"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000013508", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_002693.3(POLG):c.2869G>T (p.Ala957Ser)"}}], "canonical_spdi": "NC_000015.10:89320877:C:A", "attributes": [{"type": "HGVS, coding, RefSeq", "value": "NM_001126131.2:c.2869G>T"}, {"type": "HGVS, coding, RefSeq", "value": "NM_002693.3:c.2869G>T"}, {"type": "HGVS, genomic, LRG", "value": "LRG_765:g.18918G>T"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_008218.2:g.18918G>T"}, {"type": "HGVS, genomic, top level", "value": "NC_000015.10:g.89320878C>A", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000015.9:g.89864109C>A", "integer_value": 37}, {"type": "HGVS, protein"}, {"type": "HGVS, protein", "value": "P54098:p.Ala957Ser"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001119603.1:p.Ala957Ser"}, {"type": "HGVS, protein, RefSeq", "value": "NP_002684.1:p.Ala957Ser"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001126131.2:c.2869G>T"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_002693.3:c.2869G>T"}]}, {"type": "ProteinChange1LetterCode", "value": "A957S"}, {"type": "ProteinChange3LetterCode", "value": "ALA957SER"}], "cytogenic_locations": ["15q26.1"], "sequence_locations": [{"assembly": "GRCh38", "chr": "15", "accession": "NC_000015.10", "start": 89320878, "stop": 89320878, "display_start": 89320878, "display_stop": 89320878, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 89320878, "reference_allele_vcf": "C", "alternate_allele_vcf": "A"}, {"assembly": "GRCh37", "chr": "15", "accession": "NC_000015.9", "start": 89864109, "stop": 89864109, "display_start": 89864109, "display_stop": 89864109, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 89864109, "reference_allele_vcf": "C", "alternate_allele_vcf": "A"}], "measure_relationship": [{"type": "within multiple genes by overlap", "names": [{"value": {"type": "Preferred", "value": "DNA polymerase gamma, catalytic subunit"}}], "symbols": [{"value": {"type": "Preferred", "value": "POLG"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "15", "accession": "NC_000015.10", "start": 89316320, "stop": 89334824, "display_start": 89316320, "display_stop": 89334824, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "15", "accession": "NC_000015.9", "start": 89859535, "stop": 89878025, "display_start": 89859535, "display_stop": 89878025, "strand": "-", "variant_length": 18491, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "5428"}, {"db": "OMIM", "id": "174763", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:9179"}]}, {"type": "within multiple genes by overlap", "names": [{"value": {"type": "Preferred", "value": "POLG alternative reading frame"}}], "symbols": [{"value": {"type": "Preferred", "value": "POLGARF"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "15", "accession": "NC_000015.10", "start": 89316320, "stop": 89334824, "display_start": 89316320, "display_stop": 89334824, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}], "xrefs": [{"db": "Gene", "id": "125316803"}, {"db": "HGNC", "id": "HGNC:56246"}]}], "xrefs": [{"db": "UniProtKB", "id": "P54098#VAR_023682"}, {"db": "OMIM", "id": "174763.0014", "type": "Allelic variant"}, {"db": "dbSNP", "id": "121918051", "type": "rs"}], "id": 28547}], "names": [{"value": {"type": "Preferred", "value": "NM_002693.3(POLG):c.2869G>T (p.Ala957Ser)"}}], "xrefs": [{"db": "ClinGen", "id": "CA256895"}], "id": 13508}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0024528"}]}, {"value": {"type": "Alternate", "value": "PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL DOMINANT 1"}, "xrefs": [{"db": "OMIM", "id": "157640", "type": "MIM"}]}], "symbols": [{"value": {"type": "Alternate", "value": "PEOA1"}, "xrefs": [{"db": "OMIM", "id": "157640", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called \"chronic progressive external ophthalmoplegia plus,\" or \"CPEO+\")."}, "xrefs": [{"db": "GeneReviews", "id": "NBK26471"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301382"}, {"source": "BookShelf", "value": "NBK1203"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "PubMed", "value": "20301791"}, {"source": "BookShelf", "value": "NBK26471"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "PubMed", "value": "28749475"}, {"source": "pmc", "value": "7804217"}], "type": "general", "abbrev": "MMS, 2017"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0024528"}, {"db": "MedGen", "id": "C1834846"}, {"db": "OMIM", "id": "157640", "type": "MIM"}]}], "id": 3712}, "date_created": "2013-04-04", "date_last_updated": "2023-03-26", "id": 71965}, "record_status": "current", "title": "NM_002693.3(POLG):c.2869G>T (p.Ala957Ser) AND Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1", "clinvar_assertions": [{"id": 34713, "submission_id": {"local_key": "174763.0014_PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1", "submitter": "OMIM", "title": "POLG, ALA957SER_PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1", "submitter_date": "2016-10-11"}, "clinvar_accession": {"acc": "SCV000034713", "version": 3, "type": "SCV", "date_updated": "2016-10-14", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2002-08-01"}], "external_ids": [{"db": "OMIM", "id": "174763.0014", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In affected members of 2 PEOA1 (157640) families originating from a small village in northwest Sicily, Lamantea et al. (2002) identified a heterozygous 2869G-T transversion in the POLG gene, resulting in an ala957-to-ser (A957S) substitution. One patient in 1 of the families was homozygous for the A957S mutation and showed a more severe phenotype with earlier onset and a much higher amount of mtDNA deletions than his mildly affected heterozygous mother. Microsatellite analysis showed a common disease haplotype, supporting a common origin in these 2 families."}, "citations": [{"ids": [{"source": "PubMed", "value": "12210792"}]}], "xrefs": [{"db": "OMIM", "id": "157640", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "POLG, ALA957SER"}}], "attributes": [{"type": "NonHGVS", "value": "ALA957SER"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "POLG"}}]}], "xrefs": [{"db": "OMIM", "id": "174763.0014", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000445396", "version": 1, "type": "RCV", "date_updated": "2023-03-26", "date_created": "2017-03-14"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "uncertain significance", "date_last_evaluated": "2016-01-11"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "number_tested": 1}, "methods": ["research"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}, {"attribute": {"type": "NumberMosaic", "integer_value": 0}}, {"attribute": {"type": "SecondaryFinding", "value": "no"}}]}], "measures": {"type": "Variant", "acc": "VCV000393457", "version": 4, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.2078G>A (p.Cys693Tyr)"}}], "canonical_spdi": "NC_000002.12:47476438:G:A", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_218t1:c.2078G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001258281.1:c.1880G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000251.3:c.2078G>A"}, {"type": "HGVS, genomic, LRG", "value": "LRG_218:g.78316G>A"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_007110.2:g.78316G>A"}, {"type": "HGVS, genomic, top level", "value": "NC_000002.12:g.47476439G>A", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000002.11:g.47703578G>A", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_000251.1:c.2078G>A"}, {"type": "HGVS, previous", "value": "NM_000251.2:c.2078G>A"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein", "value": "p.C693Y"}, {"type": "HGVS, protein", "value": "LRG_218p1:p.Cys693Tyr"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001245210.1:p.Cys627Tyr"}, {"type": "HGVS, protein, RefSeq", "value": "NP_000242.1:p.Cys693Tyr"}, {"type": "HGVS, protein, RefSeq", "value": "NP_000242.1:p.Cys693Tyr"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_000251.3:c.2078G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001258281.1:c.1880G>A"}]}, {"type": "ProteinChange1LetterCode", "value": "C627Y"}, {"type": "ProteinChange1LetterCode", "value": "C693Y"}], "cytogenic_locations": ["2p21"], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 47476439, "stop": 47476439, "display_start": 47476439, "display_stop": 47476439, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 47476439, "reference_allele_vcf": "G", "alternate_allele_vcf": "A"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 47703578, "stop": 47703578, "display_start": 47703578, "display_stop": 47703578, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 47703578, "reference_allele_vcf": "G", "alternate_allele_vcf": "A"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "mutS homolog 2"}}], "symbols": [{"value": {"type": "Preferred", "value": "MSH2"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 47403067, "stop": 47709830, "display_start": 47403067, "display_stop": 47709830, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 47630205, "stop": 47710366, "display_start": 47630205, "display_stop": 47710366, "strand": "+", "variant_length": 80162, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "4436"}, {"db": "OMIM", "id": "609309", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:7325"}], "comments": [{"text": "This gene is cited in the ACMG recommendations of 2013 (PubMed 23788249) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2016 (PubMed 27854360) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2021 (SF v3.0; PubMed 34012068) for reporting secondary findings in clinical exome and genome sequencing.", "type": "public", "datasource": "ClinVar"}, {"text": "This gene is cited in the ACMG recommendations of 2022 (SF v3.1; PubMed 35802134) for reporting secondary findings in clinical exome and genome sequencing.", "type": "public", "datasource": "ClinVar"}]}], "xrefs": [{"db": "dbSNP", "id": "1057524909", "type": "rs"}], "id": 380277}], "names": [{"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.2078G>A (p.Cys693Tyr)"}}, {"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.2078G>A (p.Cys693Tyr)"}}], "xrefs": [{"db": "ClinGen", "id": "CA16609274"}], "id": 393457}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "not specified"}}, {"value": {"type": "Alternate", "value": "AllHighlyPenetrant"}}], "attributes": [{"value": {"type": "public definition", "value": "The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant."}}], "xrefs": [{"db": "MedGen", "id": "CN169374"}]}], "id": 9590}, "date_created": "2017-03-14", "date_last_updated": "2023-03-26", "id": 1030503}, "record_status": "current", "title": "NM_000251.3(MSH2):c.2078G>A (p.Cys693Tyr) AND not specified", "clinvar_assertions": [{"id": 1030461, "submission_id": {"local_key": "c.2078G>A", "submitter": "Genetic Laboratory, Instituto Nacional de Cancer", "submitted_assembly": "GRCh37", "submitter_date": "2017-01-12"}, "clinvar_accession": {"acc": "SCV000537128", "version": 1, "type": "SCV", "date_updated": "2017-03-14", "date_created": "2017-03-14", "org_id": "506064", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["uncertain significance"], "date_last_evaluated": "2016-01-11"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "number_tested": 1, "gender": "female", "family_data": {"pedigree_id": "1108"}, "proband": "yes"}, "methods": ["research"], "observed_data": [{"attribute": {"type": "NumberMosaic", "integer_value": 0}}, {"attribute": {"type": "SingleHeterozygote", "integer_value": 1}}, {"attribute": {"type": "SecondaryFinding", "value": "no"}}], "comments": [{"text": "Ascending colon cancer diagnosed at 42 years old. Immunohistochemistry demonstrated lost of MSH6 protein. Microsatellite instability for the 5 biomarkers screened (MSI-H). Suggestive of Lynch Syndrome."}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Alternate", "value": "p.C693Y"}}], "attributes": [{"type": "HGVS", "value": "NM_000251.2:c.2078G>A"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "MSH2"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "not specified"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000571689", "version": 6, "type": "RCV", "date_updated": "2023-03-26", "date_created": "2018-01-01"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, multiple submitters, no conflicts", "description": "pathogenic", "date_last_evaluated": "2020-04-02"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown", "number_tested": 1}, "methods": ["clinical testing", "clinical testing"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}, {"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000090883", "version": 8, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.2090G>T (p.Cys697Phe)"}}], "canonical_spdi": "NC_000002.12:47476450:G:T", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_218t1:c.2090G>T"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001258281.1:c.1892G>T"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000251.3:c.2090G>T"}, {"type": "HGVS, genomic, LRG", "value": "LRG_218:g.78328G>T"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_007110.2:g.78328G>T"}, {"type": "HGVS, genomic, top level", "value": "NC_000002.12:g.47476451G>T", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000002.11:g.47703590G>T", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_000251.1:c.2090G>T"}, {"type": "HGVS, previous", "value": "NM_000251.2:c.2090G>T"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein", "value": "LRG_218p1:p.Cys697Phe"}, {"type": "HGVS, protein", "value": "P43246:p.Cys697Phe"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001245210.1:p.Cys631Phe"}, {"type": "HGVS, protein, RefSeq", "value": "NP_000242.1:p.Cys697Phe"}, {"type": "HGVS, protein, RefSeq", "value": "NP_000242.1:p.Cys697Phe"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_000251.3:c.2090G>T"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001258281.1:c.1892G>T"}]}, {"type": "ProteinChange1LetterCode", "value": "C631F"}, {"type": "ProteinChange1LetterCode", "value": "C697F"}], "cytogenic_locations": ["2p21"], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 47476451, "stop": 47476451, "display_start": 47476451, "display_stop": 47476451, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 47476451, "reference_allele_vcf": "G", "alternate_allele_vcf": "T"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 47703590, "stop": 47703590, "display_start": 47703590, "display_stop": 47703590, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 47703590, "reference_allele_vcf": "G", "alternate_allele_vcf": "T"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "mutS homolog 2"}}], "symbols": [{"value": {"type": "Preferred", "value": "MSH2"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 47403067, "stop": 47709830, "display_start": 47403067, "display_stop": 47709830, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 47630205, "stop": 47710366, "display_start": 47630205, "display_stop": 47710366, "strand": "+", "variant_length": 80162, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "4436"}, {"db": "OMIM", "id": "609309", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:7325"}], "comments": [{"text": "This gene is cited in the ACMG recommendations of 2013 (PubMed 23788249) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2016 (PubMed 27854360) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2021 (SF v3.0; PubMed 34012068) for reporting secondary findings in clinical exome and genome sequencing.", "type": "public", "datasource": "ClinVar"}, {"text": "This gene is cited in the ACMG recommendations of 2022 (SF v3.1; PubMed 35802134) for reporting secondary findings in clinical exome and genome sequencing.", "type": "public", "datasource": "ClinVar"}]}], "xrefs": [{"db": "International Society for Gastrointestinal Hereditary Tumours (InSiGHT)", "id": "c.2090G>T"}, {"db": "UniProtKB", "id": "P43246#VAR_004486"}, {"db": "dbSNP", "id": "63750398", "type": "rs"}], "id": 96358}], "names": [{"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.2090G>T (p.Cys697Phe)"}}, {"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.2090G>T (p.Cys697Phe)"}}], "xrefs": [{"db": "ClinGen", "id": "CA019999"}], "id": 90883}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Hereditary cancer-predisposing syndrome"}, "xrefs": [{"db": "SNOMED CT", "id": "699346009"}]}, {"value": {"type": "Alternate", "value": "Neoplastic Syndromes, Hereditary"}, "xrefs": [{"db": "MeSH", "id": "D009386"}]}, {"value": {"type": "Alternate", "value": "Tumor predisposition"}}, {"value": {"type": "Alternate", "value": "Cancer predisposition"}, "xrefs": [{"db": "Genetic Alliance", "id": "Hereditary+Cancer/3345"}]}, {"value": {"type": "Alternate", "value": "Hereditary Cancer Syndrome"}}], "attributes": [{"value": {"type": "keyword", "value": "Neoplasm"}}, {"value": {"type": "keyword", "value": "Hereditary cancer syndrome"}}], "citations": [{"ids": [{"source": "pmc", "value": "3075918"}], "type": "general", "abbrev": "IARC, 2008"}, {"ids": [{"source": "PubMed", "value": "25394175"}], "type": "general", "abbrev": "ACMG/NSGC, 2015"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0015356"}, {"db": "MeSH", "id": "D009386"}, {"db": "MedGen", "id": "C0027672"}]}], "id": 13598}, "date_created": "2018-01-01", "date_last_updated": "2023-03-26", "id": 1323111}, "record_status": "current", "title": "NM_000251.3(MSH2):c.2090G>T (p.Cys697Phe) AND Hereditary cancer-predisposing syndrome", "clinvar_assertions": [{"id": 1305117, "submission_id": {"local_key": "a6171", "submitter": "Ambry Genetics", "submitted_assembly": "GRCh37", "submitter_date": "2022-11-11"}, "clinvar_accession": {"acc": "SCV000669699", "version": 4, "type": "SCV", "date_updated": "2022-11-29", "date_created": "2018-01-01", "org_id": "61756", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["pathogenic"], "citations": [{"ids": [{"source": "PubMed", "value": "17101317"}]}, {"ids": [{"source": "PubMed", "value": "17531815"}]}, {"ids": [{"source": "PubMed", "value": "22102614"}]}, {"ids": [{"source": "PubMed", "value": "24362816"}]}, {"ids": [{"source": "PubMed", "value": "31569399"}]}, {"ids": [{"source": "PubMed", "value": "9298827"}]}], "comments": [{"text": "The p.C697F pathogenic mutation (also known as c.2090G>T), located in coding exon 13 of the MSH2 gene, results from a G to T substitution at nucleotide position 2090. The cysteine at codon 697 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been found to have moderate segregation with disease in families that met Amsterdam criteria for Lynch syndrome. Tumor samples from at least one affected individual in each family demonstrated high microsatellite instability (Wehner M et al. Hum. Mutat., 1997;10:241-4; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17; Ollila S et al. Int. J. Oncol., 2006 Jan;28:149-53). Several studies performed with this variant demonstrated reduced mismatch repair activity when compared to wild type and defective DNA mismatch binding (Ollila S et al. Int. J. Oncol., 2006 Jan;28:149-53; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17; Drost M et al. Hum. Mutat., 2012 Mar;33:488-94; Lützen A et al. Mutat. Res., 2008 Oct;645:44-55; Ollila S et al. Hum. Mutat., 2008 Nov;29:1355-63). This alteration has also been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Nat. Genet., 2014 Feb;46:107-15). The p.C697F alteration is part of the ATPase domain, which is a structurally important region (Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). Based on internal structural analysis, this variant is significantly more destabilizing than nearby known pathogenic variants (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation."}], "date_last_evaluated": "2020-04-02"}], "external_ids": [{"db": "Ambry Genetics", "id": "a6171"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "Ambry General Variant Classification Scheme_2022"}, "citations": [{"url": "https://submit.ncbi.nlm.nih.gov/ft/byid/5hsvndk6/ambry_general_variant_classification_scheme_2022.pdf"}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown", "number_tested": 1}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "VariantAlleles", "integer_value": 1}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_000251.1:c.2090G>T"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "MSH2"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "MedGen", "id": "C0027672", "type": "CUI"}]}]}}, {"id": 2662855, "submission_id": {"local_key": "Db4KrQBSZeoE7-orUyypkcChGU154SMr11OHlHwLRns|MedGen:C0027672", "submitter": "Color Diagnostics, LLC DBA Color Health", "submitted_assembly": "GRCh37", "submitter_date": "2022-01-10"}, "clinvar_accession": {"acc": "SCV001354540", "version": 2, "type": "SCV", "date_updated": "2022-01-12", "date_created": "2020-06-22", "org_id": "505849", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["pathogenic"], "comments": [{"text": "This missense variant replaces cysteine with phenylalanine at codon 697 of the MSH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes deficient mismatch repair activity, reduced protein expression, and abnormal cellular localization (PMID: 10469597, 16327991, 17101317, 17720936, 18822302, 18951462, 22102614). This variant has been reported in more than 10 individuals affected with colorectal cancer, endometrial cancer, and sebaceous carcinoma (PMID: 10323887, 11231323, 11859205, 12436451, 15235030, 16327991, 17101317, 18566915, 9298827). Microsatellite instability has been demonstrated in more than 5 tumor samples from these individuals (PMID: 11231323, 11859205, 12436451, 16327991, 17101317). Immunohistochemistry has demonstrated loss of MSH2 protein expression in more than 5 tumor samples (PMID: 11859205, 12436451, 15235030, 16327991, 17101317). Different variants affecting the same position (p.Cys697Tyr and p.Cys697Arg) are considered to be disease-causing (ClinVar variation ID: 187518 and 90882), suggesting that cysteine at this position is important for protein structure and function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic."}], "date_last_evaluated": "2019-07-03"}], "external_ids": [{"db": "Color Health, Inc", "id": "Db4KrQBSZeoE7-orUyypkcChGU154SMr11OHlHwLRns"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "ACMG Guidelines, 2015"}, "citations": [{"ids": [{"source": "PubMed", "value": "25741868"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_000251.2:c.2090G>T"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "MSH2"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "MedGen", "id": "C0027672", "type": "CUI"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000774575", "version": 4, "type": "RCV", "date_updated": "2023-03-26", "date_created": "2019-05-20"}, "record_status": "current", "clinical_significance": {"review_status": "criteria provided, single submitter", "description": "likely pathogenic", "date_last_evaluated": "2020-06-15"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "acc": "VCV000090790", "version": 8, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.1807G>A (p.Asp603Asn)"}}], "canonical_spdi": "NC_000002.12:47475071:G:A", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_218t1:c.1807G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001258281.1:c.1609G>A"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000251.3:c.1807G>A"}, {"type": "HGVS, genomic, LRG", "value": "LRG_218:g.76949G>A"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_007110.2:g.76949G>A"}, {"type": "HGVS, genomic, top level", "value": "NC_000002.12:g.47475072G>A", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000002.11:g.47702211G>A", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_000251.1:c.1807G>A"}, {"type": "HGVS, previous", "value": "NM_000251.2:c.1807G>A"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein", "value": "LRG_218p1:p.Asp603Asn"}, {"type": "HGVS, protein", "value": "P43246:p.Asp603Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001245210.1:p.Asp537Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_000242.1:p.Asp603Asn"}, {"type": "HGVS, protein, RefSeq", "value": "NP_000242.1:p.Asp603Asn"}, {"type": "Location", "value": "NM_000251.2:exon 12"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_000251.3:c.1807G>A"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001258281.1:c.1609G>A"}]}, {"type": "ProteinChange1LetterCode", "value": "D537N"}, {"type": "ProteinChange1LetterCode", "value": "D603N"}], "cytogenic_locations": ["2p21"], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 47475072, "stop": 47475072, "display_start": 47475072, "display_stop": 47475072, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 47475072, "reference_allele_vcf": "G", "alternate_allele_vcf": "A"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 47702211, "stop": 47702211, "display_start": 47702211, "display_stop": 47702211, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 47702211, "reference_allele_vcf": "G", "alternate_allele_vcf": "A"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "mutS homolog 2"}}], "symbols": [{"value": {"type": "Preferred", "value": "MSH2"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "2", "accession": "NC_000002.12", "start": 47403067, "stop": 47709830, "display_start": 47403067, "display_stop": 47709830, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "2", "accession": "NC_000002.11", "start": 47630205, "stop": 47710366, "display_start": 47630205, "display_stop": 47710366, "strand": "+", "variant_length": 80162, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "4436"}, {"db": "OMIM", "id": "609309", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:7325"}], "comments": [{"text": "This gene is cited in the ACMG recommendations of 2013 (PubMed 23788249) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2016 (PubMed 27854360) for reporting incidental findings in exons.", "type": "public", "datasource": "NCBI curation"}, {"text": "This gene is cited in the ACMG recommendations of 2021 (SF v3.0; PubMed 34012068) for reporting secondary findings in clinical exome and genome sequencing.", "type": "public", "datasource": "ClinVar"}, {"text": "This gene is cited in the ACMG recommendations of 2022 (SF v3.1; PubMed 35802134) for reporting secondary findings in clinical exome and genome sequencing.", "type": "public", "datasource": "ClinVar"}]}], "xrefs": [{"db": "International Society for Gastrointestinal Hereditary Tumours (InSiGHT)", "id": "c.1807G>A"}, {"db": "UniProtKB", "id": "P43246#VAR_043772"}, {"db": "dbSNP", "id": "63750657", "type": "rs"}], "id": 96265}], "names": [{"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.1807G>A (p.Asp603Asn)"}}, {"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.1807G>A (p.Asp603Asn)"}}, {"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.1807G>A (p.Asp603Asn)"}}, {"value": {"type": "Preferred", "value": "NM_000251.3(MSH2):c.1807G>A (p.Asp603Asn)"}}], "xrefs": [{"db": "ClinGen", "id": "CA019349"}], "id": 90790}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Hereditary cancer-predisposing syndrome"}, "xrefs": [{"db": "SNOMED CT", "id": "699346009"}]}, {"value": {"type": "Alternate", "value": "Neoplastic Syndromes, Hereditary"}, "xrefs": [{"db": "MeSH", "id": "D009386"}]}, {"value": {"type": "Alternate", "value": "Tumor predisposition"}}, {"value": {"type": "Alternate", "value": "Cancer predisposition"}, "xrefs": [{"db": "Genetic Alliance", "id": "Hereditary+Cancer/3345"}]}, {"value": {"type": "Alternate", "value": "Hereditary Cancer Syndrome"}}], "attributes": [{"value": {"type": "keyword", "value": "Neoplasm"}}, {"value": {"type": "keyword", "value": "Hereditary cancer syndrome"}}], "citations": [{"ids": [{"source": "pmc", "value": "3075918"}], "type": "general", "abbrev": "IARC, 2008"}, {"ids": [{"source": "PubMed", "value": "25394175"}], "type": "general", "abbrev": "ACMG/NSGC, 2015"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0015356"}, {"db": "MeSH", "id": "D009386"}, {"db": "MedGen", "id": "C0027672"}]}], "id": 13598}, "date_created": "2019-05-20", "date_last_updated": "2023-03-26", "id": 1785717}, "record_status": "current", "title": "NM_000251.3(MSH2):c.1807G>A (p.Asp603Asn) AND Hereditary cancer-predisposing syndrome", "clinvar_assertions": [{"id": 1776272, "submission_id": {"local_key": "Db4KrQBSZeoE7-orUyypkT-VDv1GpncYQc6tyaOK__s|MedGen:C0027672", "submitter": "Color Diagnostics, LLC DBA Color Health", "submitted_assembly": "GRCh37", "submitter_date": "2021-06-11"}, "clinvar_accession": {"acc": "SCV000908317", "version": 3, "type": "SCV", "date_updated": "2021-06-19", "date_created": "2019-05-20", "org_id": "505849", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["likely pathogenic"], "comments": [{"text": "This missense variant replaces aspartic acid with asparagine at codon 603 in the MSH3/MSH6 interaction domain of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mismatch repair activity in yeast and mammalian cell-based assays (PMID: 17101317, 17720936, 26951660). This is a recurrent variant in the Finnish population and has been reported in several Finnish families affected with Lynch syndrome or Lynch syndrome-associated cancers (PMID: 10829038, 15837969, 17043646, 17101317, 17267619, 23544471). Microsatellite instability has been demonstrated in multiple tumor samples from these individuals (PMID: 15837969, 17101317, 17267619). Immunohistochemistry has demonstrated loss of MSH2 protein expression in multiple tumor samples (PMID: 15837969, 17101317). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic."}], "date_last_evaluated": "2020-06-15"}], "external_ids": [{"db": "Color Health, Inc", "id": "Db4KrQBSZeoE7-orUyypkT-VDv1GpncYQc6tyaOK__s"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "ACMG Guidelines, 2015"}, "citations": [{"ids": [{"source": "PubMed", "value": "25741868"}]}]}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "unknown"}, "methods": ["clinical testing"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NM_000251.2:c.1807G>A"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "MSH2"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"xrefs": [{"db": "MedGen", "id": "C0027672", "type": "CUI"}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000012959", "version": 3, "type": "RCV", "date_updated": "2023-06-10", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2002-09-01"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In 3 unrelated Brazilian patients with the classic form of the 21-hydroxylase deficiency (201910), Billerbeck et al. (2002) found 3 novel mutations after CYP21 gene sequencing. In 1 patient and her brother, both affected with the simple virilizing form, and in their aunt, with the nonclassic form, an AG-to-GG transition was found in the acceptor site of intron 2. In the sibs, this mutation was found in compound heterozygosity with the I172N mutation (613815.0001); in their aunt, it was found in compound heterozygosity with P30L (613815.0004), which confers more than 30% enzyme activity, explaining why she presented with the nonclassic form. In another patient with the salt-wasting form, they found an insertion of an adenine between nucleotides 1003 and 1004, in exon 4, that altered the reading frame and created a stop codon at codon 297 (613815.0029). In the third patient and his sister, they found a C-to-T transition in codon 408 predicted to encode an arg408-to-cys (R408C) substitution in a region where arginine is conserved in at least 4 different species. Microsatellite studies, using markers flanking CYP21 gene, revealed that each new mutation presents the same haplotype, suggesting a gene founder effect for each one."}, "citations": [{"ids": [{"source": "PubMed", "value": "12213891"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000012177", "version": 1, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_000500.9(CYP21A2):c.293-2A>G"}}], "canonical_spdi": "NC_000006.12:32039091:A:G", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_829t1:c.293-2A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001368143.2:c.-115A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001368144.2:c.-115A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001128590.4:c.203-2A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_000500.9:c.293-2A>G"}, {"type": "HGVS, genomic, LRG", "value": "LRG_829:g.5788A>G"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_045215.1:g.1321A>G"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_007941.3:g.5788A>G"}, {"type": "HGVS, genomic, top level", "value": "NC_000006.12:g.32039092A>G", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000006.11:g.32006869A>G", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_000500.7:c.293-2A>G"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein"}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001368143.2:c.-115A>G"}]}, {"type": "MolecularConsequence", "value": "5 prime UTR variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001623"}, {"db": "RefSeq", "id": "NM_001368144.2:c.-115A>G"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_000500.9:c.293-2A>G"}]}, {"type": "MolecularConsequence", "value": "splice acceptor variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001574"}, {"db": "RefSeq", "id": "NM_001128590.4:c.203-2A>G"}]}, {"type": "nucleotide change", "value": "IVS2, A-G, -2"}], "cytogenic_locations": ["6p21.33"], "sequence_locations": [{"assembly": "GRCh38", "chr": "6", "accession": "NC_000006.12", "start": 32039092, "stop": 32039092, "display_start": 32039092, "display_stop": 32039092, "variant_length": 1, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current", "position_vcf": 32039092, "reference_allele_vcf": "A", "alternate_allele_vcf": "G"}, {"assembly": "GRCh37", "chr": "6", "accession": "NC_000006.11", "start": 32006869, "stop": 32006869, "display_start": 32006869, "display_stop": 32006869, "variant_length": 1, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous", "position_vcf": 32006869, "reference_allele_vcf": "A", "alternate_allele_vcf": "G"}], "measure_relationship": [{"type": "within multiple genes by overlap", "names": [{"value": {"type": "Preferred", "value": "CYP21A2 recombination region"}}], "symbols": [{"value": {"type": "Preferred", "value": "LOC106780800"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "6", "accession": "NC_000006.12", "start": 32037872, "stop": 32041144, "display_start": 32037872, "display_stop": 32041144, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh38", "chr": "6", "accession": "NT_167247.2", "start": 3379909, "stop": 3383177, "display_start": 3379909, "display_stop": 3383177, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}], "xrefs": [{"db": "Gene", "id": "106780800"}]}, {"type": "within multiple genes by overlap", "names": [{"value": {"type": "Preferred", "value": "cytochrome P450 family 21 subfamily A member 2"}}], "symbols": [{"value": {"type": "Preferred", "value": "CYP21A2"}}], "sequence_locations": [{"assembly": "GRCh38", 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"accession": "NT_167249.2", "start": 3339605, "stop": 3342831, "display_start": 3339605, "display_stop": 3342831, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh38", "chr": "6", "accession": "NT_167248.2", "start": 3261650, "stop": 3264877, "display_start": 3261650, "display_stop": 3264877, "strand": "+", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "6", "accession": "NC_000006.11", "start": 32006092, "stop": 32009446, "display_start": 32006092, "display_stop": 32009446, "strand": "+", "variant_length": 3355, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "1589"}, {"db": "OMIM", "id": "613815", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:2600"}]}], "xrefs": [{"db": "OMIM", "id": "613815.0028", "type": "Allelic variant"}, {"db": "dbSNP", "id": "1582302625", "type": "rs"}], "comments": [{"text": "ClinGen staff contributed the HGVS expression for this variant.", "type": "public", "datasource": "ClinGen"}], "id": 27216}], "names": [{"value": {"type": "Preferred", "value": "NM_000500.9(CYP21A2):c.293-2A>G"}}], "id": 12177}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0008728"}, {"db": "Orphanet", "id": "90794"}, {"db": "SNOMED CT", "id": "717261006"}]}, {"value": {"type": "Alternate", "value": "Congenital adrenal hyperplasia due to 21-hydroxylase deficiency"}}, {"value": {"type": "Alternate", "value": "CYP21 deficiency"}}, {"value": {"type": "Alternate", "value": "21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia"}, "xrefs": [{"db": "GeneReviews", "id": "NBK1171"}]}], "attributes": [{"value": {"type": "public definition", "value": "21-hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex. In 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilization in all individuals and salt wasting in some individuals. A classic form with severe enzyme deficiency and prenatal onset of virilization is distinguished from a non-classic form with mild enzyme deficiency and postnatal onset. The classic form is further divided into the simple virilizing form (~25% of affected individuals) and the salt-wasting form, in which aldosterone production is inadequate (\u226575% of individuals). Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises. Individuals with the non-classic form of 21-OHD CAH present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1171"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301350"}, {"source": "BookShelf", "value": "NBK1171"}], "type": "review", "abbrev": "GeneReviews"}, {"type": "practice guideline", "abbrev": "ACMG ACT Sheet, 2011", "url": "https://www.ncbi.nlm.nih.gov/books/NBK55827/bin/CAH.pdf", "citation_text": "American College of Medical Genetics ACT SHEET, Congenital Adrenal Hyperplasia, 2011"}, {"type": "practice guideline", "abbrev": "ACMG Algorithm, 2009", "url": "https://www.ncbi.nlm.nih.gov/books/NBK55827/bin/Visio-NBS_Elevated_17OHP.pdf", "citation_text": "American College of Medical Genetics Algorithm, Congenital Adrenal Hyperplasia, 2009"}, {"ids": [{"source": "pmc", "value": "2936060"}], "type": "general", "abbrev": "ESCGS, 2010"}, {"ids": [{"source": "PubMed", "value": "30272171"}, {"source": "pmc", "value": "6456929"}], "type": "general", "abbrev": "ES, 2018"}, {"type": "practice guideline", "abbrev": "ACMG Algorithm, 2009", "url": "https://www.acmg.net/PDFLibrary/Elevated-17-OHP-Algorithm.pdf", "citation_text": "American College of Medical Genetics and Genomics, Algorithm, Congenital Adrenal Hyperplasia (Elevated 17-OHP), 2009"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0008728"}, {"db": "MedGen", "id": "C2936858"}, {"db": "Orphanet", "id": "90794"}, {"db": "OMIM", "id": "201910", "type": "MIM"}]}], "id": 3295}, "date_created": "2013-04-04", "date_last_updated": "2023-06-10", "id": 70462}, "record_status": "current", "title": "NM_000500.9(CYP21A2):c.293-2A>G AND Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", "clinvar_assertions": [{"id": 33203, "submission_id": {"local_key": "613815.0028_ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY, CLASSIC TYPE", "submitter": "OMIM", "title": "CYP21A2, IVS2, A-G, -2_ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY, CLASSIC TYPE", "submitter_date": "2016-04-06"}, "clinvar_accession": {"acc": "SCV000033203", "version": 2, "type": "SCV", "date_updated": "2016-04-08", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2002-09-01"}], "external_ids": [{"db": "OMIM", "id": "613815.0028", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In 3 unrelated Brazilian patients with the classic form of the 21-hydroxylase deficiency (201910), Billerbeck et al. (2002) found 3 novel mutations after CYP21 gene sequencing. In 1 patient and her brother, both affected with the simple virilizing form, and in their aunt, with the nonclassic form, an AG-to-GG transition was found in the acceptor site of intron 2. In the sibs, this mutation was found in compound heterozygosity with the I172N mutation (613815.0001); in their aunt, it was found in compound heterozygosity with P30L (613815.0004), which confers more than 30% enzyme activity, explaining why she presented with the nonclassic form. In another patient with the salt-wasting form, they found an insertion of an adenine between nucleotides 1003 and 1004, in exon 4, that altered the reading frame and created a stop codon at codon 297 (613815.0029). In the third patient and his sister, they found a C-to-T transition in codon 408 predicted to encode an arg408-to-cys (R408C) substitution in a region where arginine is conserved in at least 4 different species. Microsatellite studies, using markers flanking CYP21 gene, revealed that each new mutation presents the same haplotype, suggesting a gene founder effect for each one."}, "citations": [{"ids": [{"source": "PubMed", "value": "12213891"}]}], "xrefs": [{"db": "OMIM", "id": "201910", "type": "MIM"}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "CYP21A2, IVS2, A-G, -2"}}], "attributes": [{"type": "NonHGVS", "value": "IVS2, A-G, -2"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "CYP21A2"}}]}], "xrefs": [{"db": "OMIM", "id": "613815.0028", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY, CLASSIC TYPE"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000014439", "version": 20, "type": "RCV", "date_updated": "2023-06-10", "date_created": "2013-04-04"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2004-09-04"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In affected members of a 3-generation Belgian pedigree with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (157640), Van Goethem et al. (2001) identified a 2864A-G transition in the POLG gene, resulting in a tyr955-to-cys (Y955C) substitution in the polymerase B domain of the protein. The tyrosine at codon 955 is highly conserved. Segregation analysis showed complete cosegregation of Y955C with autosomal dominant PEO (maximum lod = 4.01 at theta = 0.0). The mutation was present in the 8 patients and 2 of 15 at-risk individuals; it was absent in 432 control chromosomes."}, "citations": [{"ids": [{"source": "PubMed", "value": "11431686"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "Lamantea et al. (2002) identified the heterozygous Y955C mutation in 5 unrelated families with adPEO. Four families were Italian and 1 was from Greece; 1 of the Italian families was originally reported by Zeviani et al. (1989) and Servidei et al. (1991). Microsatellite analysis did not identify a common disease haplotype in these families."}, "citations": [{"ids": [{"source": "PubMed", "value": "12210792"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": "2067633"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": "2725645"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "To analyze the effects of the Y955C mutation on the kinetics and fidelity of DNA synthesis, Ponamarev et al. (2002) expressed the Y955C mutant protein in Sf9 cells by site-directed mutagenesis. The Y955C enzyme retained a wildtype catalytic rate and demonstrated a 45-fold decrease in apparent binding affinity for the incoming nucleoside triphosphate, but the authors noted that mitochondrial matrix pools are usually high enough to overcome this reduced affinity. Fidelity studies showed that the Y955C derivative was 2-fold less accurate for basepair substitutions than wildtype, even with proofreading activity. Genetic inactivation of the exonuclease revealed a 10- to 100-fold increase in mismatch errors. Ponamarev et al. (2002) presented a model in which the enhanced error rate of the mutant enzyme promotes mtDNA deletions, as seen in PEO, via a slippage mechanism."}, "citations": [{"ids": [{"source": "PubMed", "value": "11897778"}], "type": "general"}]}, {"attribute": {"type": "Description", "value": "In affected members of 4 adPEO families, including the Swedish family originally reported by Lundberg (1962), Luoma et al. (2004) identified the heterozygous Y955C mutation."}, "citations": [{"ids": [{"source": "PubMed", "value": "14467368"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": "15351195"}], "type": "general"}]}]}], "measures": {"type": "Variant", "acc": "VCV000013495", "version": 12, "measures": [{"type": "single nucleotide variant", "names": [{"value": {"type": "Preferred", "value": "NM_002693.3(POLG):c.2864A>G (p.Tyr955Cys)"}}], "canonical_spdi": "NC_000015.10:89320882:T:C", "attributes": [{"type": "HGVS, coding, LRG", "value": "LRG_765t1:c.2864A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_001126131.2:c.2864A>G"}, {"type": "HGVS, coding, RefSeq", "value": "NM_002693.3:c.2864A>G"}, {"type": "HGVS, genomic, LRG", "value": "LRG_765:g.18913A>G"}, {"type": "HGVS, genomic, RefSeqGene", "value": "NG_008218.2:g.18913A>G"}, {"type": "HGVS, genomic, top level", "value": "NC_000015.10:g.89320883T>C", "integer_value": 38}, {"type": "HGVS, genomic, top level, previous", "value": "NC_000015.9:g.89864114T>C", "integer_value": 37}, {"type": "HGVS, previous", "value": "NM_002693.2:c.2864A>G"}, {"type": "HGVS, protein"}, {"type": "HGVS, protein", "value": "LRG_765p1:p.Tyr955Cys"}, {"type": "HGVS, protein", "value": "P54098:p.Tyr955Cys"}, {"type": "HGVS, protein, RefSeq", "value": "NP_001119603.1:p.Tyr955Cys"}, {"type": "HGVS, protein, RefSeq", "value": "NP_002684.1:p.Tyr955Cys"}, {"type": "HGVS, protein, RefSeq", "value": "NP_002684.1:p.Tyr955Cys"}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_001126131.2:c.2864A>G"}]}, {"type": "MolecularConsequence", "value": "missense variant", "xrefs": [{"db": "Sequence Ontology", "id": "SO:0001583"}, {"db": "RefSeq", "id": "NM_002693.3:c.2864A>G"}]}, {"type": "ProteinChange1LetterCode", "value": "Y955C"}, {"type": "ProteinChange3LetterCode", "value": "TYR955CYS"}], "cytogenic_locations": ["15q26.1"], "sequence_locations": 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"NC_000015.10", "start": 89316320, "stop": 89334824, "display_start": 89316320, "display_stop": 89334824, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "15", "accession": "NC_000015.9", "start": 89859535, "stop": 89878025, "display_start": 89859535, "display_stop": 89878025, "strand": "-", "variant_length": 18491, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "5428"}, {"db": "OMIM", "id": "174763", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:9179"}]}, {"type": "within multiple genes by overlap", "names": [{"value": {"type": "Preferred", "value": "POLG alternative reading frame"}}], "symbols": [{"value": {"type": "Preferred", "value": "POLGARF"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "15", "accession": "NC_000015.10", "start": 89316320, "stop": 89334824, "display_start": 89316320, "display_stop": 89334824, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}], "xrefs": [{"db": "Gene", "id": "125316803"}, {"db": "HGNC", "id": "HGNC:56246"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "28812649"}], "type": "general"}], "xrefs": [{"db": "UniProtKB", "id": "P54098#VAR_012156"}, {"db": "OMIM", "id": "174763.0001", "type": "Allelic variant"}, {"db": "dbSNP", "id": "113994099", "type": "rs"}], "id": 28534}], "names": [{"value": {"type": "Preferred", "value": "NM_002693.3(POLG):c.2864A>G (p.Tyr955Cys)"}}, {"value": {"type": "Preferred", "value": "NM_002693.3(POLG):c.2864A>G (p.Tyr955Cys)"}}, {"value": {"type": "Preferred", "value": "NM_002693.3(POLG):c.2864A>G (p.Tyr955Cys)"}}, {"value": {"type": "Preferred", "value": "NM_002693.3(POLG):c.2864A>G (p.Tyr955Cys)"}}], "attributes": [{"type": "SubmitterVariantId", "value": "GDX:652758"}], "xrefs": [{"db": "ClinGen", "id": "CA341291"}], "id": 13495}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1"}, "xrefs": [{"db": "MONDO", "id": "MONDO:0024528"}]}, {"value": {"type": "Alternate", "value": "PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL DOMINANT 1"}, "xrefs": [{"db": "OMIM", "id": "157640", "type": "MIM"}]}], "symbols": [{"value": {"type": "Alternate", "value": "PEOA1"}, "xrefs": [{"db": "OMIM", "id": "157640", "type": "MIM"}]}], "attributes": [{"value": {"type": "public definition", "value": "POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called \"chronic progressive external ophthalmoplegia plus,\" or \"CPEO+\")."}, "xrefs": [{"db": "GeneReviews", "id": "NBK26471"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301382"}, {"source": "BookShelf", "value": "NBK1203"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "PubMed", "value": "20301791"}, {"source": "BookShelf", "value": "NBK26471"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "PubMed", "value": "28749475"}, {"source": "pmc", "value": "7804217"}], "type": "general", "abbrev": "MMS, 2017"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0024528"}, {"db": "MedGen", "id": "C1834846"}, {"db": "OMIM", "id": "157640", "type": "MIM"}]}], "id": 3712}, "date_created": "2013-04-04", "date_last_updated": "2023-06-10", "id": 71942}, "record_status": "current", "title": "NM_002693.3(POLG):c.2864A>G (p.Tyr955Cys) AND Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1", "clinvar_assertions": [{"id": 34688, "submission_id": {"local_key": "174763.0001_PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1", "submitter": "OMIM", "title": "POLG, TYR955CYS_PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1", "submitter_date": "2016-10-11"}, "clinvar_accession": {"acc": "SCV000034688", "version": 3, "type": "SCV", "date_updated": "2015-10-11", "date_created": "2013-04-04", "org_id": "3", "org_type": "primary", "org_category": "resource"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "date_last_evaluated": "2004-09-04"}], "external_ids": [{"db": "OMIM", "id": "174763.0001", "type": "Allelic variant"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human"}, "affected_status": "not provided"}, "methods": ["literature only"], "observed_data": [{"attribute": {"type": "Description", "value": "In affected members of a 3-generation Belgian pedigree with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (157640), Van Goethem et al. (2001) identified a 2864A-G transition in the POLG gene, resulting in a tyr955-to-cys (Y955C) substitution in the polymerase B domain of the protein. The tyrosine at codon 955 is highly conserved. Segregation analysis showed complete cosegregation of Y955C with autosomal dominant PEO (maximum lod = 4.01 at theta = 0.0). The mutation was present in the 8 patients and 2 of 15 at-risk individuals; it was absent in 432 control chromosomes."}, "citations": [{"ids": [{"source": "PubMed", "value": "11431686"}]}], "xrefs": [{"db": "OMIM", "id": "157640", "type": "MIM"}]}, {"attribute": {"type": "Description", "value": "Lamantea et al. (2002) identified the heterozygous Y955C mutation in 5 unrelated families with adPEO. Four families were Italian and 1 was from Greece; 1 of the Italian families was originally reported by Zeviani et al. (1989) and Servidei et al. (1991). Microsatellite analysis did not identify a common disease haplotype in these families."}, "citations": [{"ids": [{"source": "PubMed", "value": "12210792"}]}, {"ids": [{"source": "PubMed", "value": "2725645"}]}, {"ids": [{"source": "PubMed", "value": "2067633"}]}]}, {"attribute": {"type": "Description", "value": "To analyze the effects of the Y955C mutation on the kinetics and fidelity of DNA synthesis, Ponamarev et al. (2002) expressed the Y955C mutant protein in Sf9 cells by site-directed mutagenesis. The Y955C enzyme retained a wildtype catalytic rate and demonstrated a 45-fold decrease in apparent binding affinity for the incoming nucleoside triphosphate, but the authors noted that mitochondrial matrix pools are usually high enough to overcome this reduced affinity. Fidelity studies showed that the Y955C derivative was 2-fold less accurate for basepair substitutions than wildtype, even with proofreading activity. Genetic inactivation of the exonuclease revealed a 10- to 100-fold increase in mismatch errors. Ponamarev et al. (2002) presented a model in which the enhanced error rate of the mutant enzyme promotes mtDNA deletions, as seen in PEO, via a slippage mechanism."}, "citations": [{"ids": [{"source": "PubMed", "value": "11897778"}]}]}, {"attribute": {"type": "Description", "value": "In affected members of 4 adPEO families, including the Swedish family originally reported by Lundberg (1962), Luoma et al. (2004) identified the heterozygous Y955C mutation."}, "citations": [{"ids": [{"source": "PubMed", "value": "14467368"}]}, {"ids": [{"source": "PubMed", "value": "15351195"}]}]}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Preferred", "value": "POLG, TYR955CYS"}}], "attributes": [{"type": "NonHGVS", "value": "TYR955CYS"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "POLG"}}]}], "xrefs": [{"db": "OMIM", "id": "174763.0001", "type": "Allelic variant"}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1"}}]}]}}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000498744", "version": 1, "type": "RCV", "date_updated": "2022-09-03", "date_created": "2017-08-20"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2017-03-27"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes"}, "methods": ["research"], "observed_data": [{"attribute": {"type": "VariantChromosomes", "integer_value": 6}}]}], "measures": {"type": "Variant", "acc": "VCV000427717", "version": 1, "measures": [{"type": "duplication", "names": [{"value": {"type": "Preferred", "value": "NM_019098.4(CNGB3):c.852+4013_903+1698dup"}}], "attributes": [{"type": "HGVS, genomic, top level", "value": "NC_000008.11:g.86652314_86662912dup", "integer_value": 38}, {"type": "HGVS, previous", "value": "NM_019098.4:c.852+4013_903+1698dup"}], "cytogenic_locations": ["8q21.3"], "sequence_locations": [{"assembly": "GRCh38", "chr": "8", "accession": "NC_000008.11", "start": 86652314, "stop": 86662912, "display_start": 86652314, "display_stop": 86662912, "variant_length": 10599, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "cyclic nucleotide gated channel subunit beta 3"}}], "symbols": [{"value": {"type": "Preferred", "value": "CNGB3"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "8", "accession": "NC_000008.11", "start": 86574179, "stop": 86743634, "display_start": 86574179, "display_stop": 86743634, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "8", "accession": "NC_000008.10", "start": 87586162, "stop": 87755902, "display_start": 87586162, "display_stop": 87755902, "strand": "-", "variant_length": 169741, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "54714"}, {"db": "OMIM", "id": "605080", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:2153"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "28795510"}], "type": "general"}], "id": 417121}], "names": [{"value": {"type": "Preferred", "value": "NM_019098.4(CNGB3):c.852+4013_903+1698dup"}}], "id": 427717}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Achromatopsia 3"}, "xrefs": [{"db": "Genetic Alliance", "id": "Achromatopsia+3/117"}, {"db": "MONDO", "id": "MONDO:0009875"}]}, {"value": {"type": "Alternate", "value": "ROD MONOCHROMACY 1"}, "xrefs": [{"db": "OMIM", "id": "262300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "ROD MONOCHROMATISM 1"}, "xrefs": [{"db": "OMIM", "id": "262300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Pingelapese blindness"}}, {"value": {"type": "Alternate", "value": "Achromatopsia with myopia"}}, {"value": {"type": "Alternate", "value": "Total colorblindness with myopia"}}, {"value": {"type": "Alternate", "value": "ACHM1 (formerly)"}}, {"value": {"type": "Alternate", "value": "Rod monochromatism 1 (formerly)"}}, {"value": {"type": "Alternate", "value": "Rod monochromacy 1 (formerly)"}}, {"value": {"type": "Alternate", "value": "RMCH1 (formerly)"}}], "symbols": [{"value": {"type": "Preferred", "value": "ACHM3"}, "xrefs": [{"db": "OMIM", "id": "262300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "ACHM1"}, "xrefs": [{"db": "OMIM", "id": "262300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "RMCH1"}, "xrefs": [{"db": "OMIM", "id": "262300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "CNGB3"}}], "attributes": [{"value": {"type": "public definition", "value": "Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. All individuals with achromatopsia (achromats) have impaired color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). Most individuals have complete achromatopsia, with total lack of function of all three types of cones. Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning. The manifestations are similar to those of individuals with complete achromatopsia, but generally less severe. Hyperopia is common in achromatopsia. Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time; both nystagmus and sensitivity to bright light may improve slightly. Although the fundus is usually normal, macular changes (which may show early signs of progression) and vessel narrowing may be present in some affected individuals. Defects in the macula are visible on optical coherence tomography."}, "xrefs": [{"db": "GeneReviews", "id": "NBK1418"}]}, {"value": {"type": "GARD id"}, "xrefs": [{"db": "Office of Rare Diseases", "id": "9650"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "20301591"}, {"source": "BookShelf", "value": "NBK1418"}], "type": "review", "abbrev": "GeneReviews"}, {"ids": [{"source": "pmc", "value": "3110037"}], "type": "Translational/Evidence-based", "abbrev": "EuroGentest, 2011"}], "xrefs": [{"db": "MONDO", "id": "MONDO:0009875"}, {"db": "MedGen", "id": "C1849792"}, {"db": "Orphanet", "id": "49382"}, {"db": "OMIM", "id": "262300", "type": "MIM"}]}], "id": 1447}, "date_created": "2017-08-20", "date_last_updated": "2022-09-03", "id": 1146329}, "record_status": "current", "title": "NM_019098.4(CNGB3):c.852+4013_903+1698dup AND Achromatopsia 3", "clinvar_assertions": [{"id": 1127643, "submission_id": {"local_key": "NC_000008.11:g.86652314_86662912dup|ACHM3", "submitter": "Molecular Genetics Laboratory, Institute for Ophthalmic Research", "submitted_assembly": "GRCh38", "submitter_date": "2017-04-06"}, "clinvar_accession": {"acc": "SCV000575866", "version": 1, "type": "SCV", "date_updated": "2017-08-20", "date_created": "2017-08-20", "org_id": "22949", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "no assertion criteria provided", "descriptions": ["pathogenic"], "citations": [{"ids": [{"source": "PubMed", "value": "28795510"}], "type": "general"}], "date_last_evaluated": "2017-03-27"}], "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes"}, "methods": ["research"], "observed_data": [{"attribute": {"type": "VariantChromosomes", "integer_value": 6}}]}], "measures": {"type": "Variant", "measures": [{"type": "variation", "names": [{"value": {"type": "Alternate", "value": "NM_019098.4:c.852+4013_903+1698dup"}}], "attributes": [{"type": "HGVS", "value": "NC_000008.11:g.86652314_86662912dup"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "CNGB3"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "ACHM3"}}]}]}, "citations": [{"ids": [{"source": "PubMed", "value": "28795510"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": "28795510"}], "type": "general"}], "comments": [{"text": "Tandem duplication of exon 7"}]}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000498740", "version": 1, "type": "RCV", "date_updated": "2023-06-17", "date_created": "2017-08-20"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2017-03-27"}, "assertion": "variation to disease", "observed_in": [{"sample": {"origin": "germline", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes"}, "methods": ["research"], "observed_data": [{"attribute": {"type": "VariantChromosomes", "integer_value": 3}}]}], "measures": {"type": "Variant", "acc": "VCV000430672", "version": 1, "measures": [{"type": "insertion", "names": [{"value": {"type": "Preferred", "value": "NC_000008.11:g.86688947_86688948ins[MF045863.1:g.1_36978]"}}], "attributes": [{"type": "HGVS, genomic, top level", "value": "NC_000008.11:g.86688947_86688948ins[MF045863.1:g.1_36978]", "integer_value": 38}], "cytogenic_locations": ["8q21.3"], "sequence_locations": [{"assembly": "GRCh38", "chr": "8", "accession": "NC_000008.11", "start": 86688947, "stop": 86688948, "display_start": 86688947, "display_stop": 86688948, "variant_length": 36978, "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}], "measure_relationship": [{"type": "within single gene", "names": [{"value": {"type": "Preferred", "value": "cyclic nucleotide gated channel subunit beta 3"}}], "symbols": [{"value": {"type": "Preferred", "value": "CNGB3"}}], "sequence_locations": [{"assembly": "GRCh38", "chr": "8", "accession": "NC_000008.11", "start": 86574179, "stop": 86743634, "display_start": 86574179, "display_stop": 86743634, "strand": "-", "assembly_accession_version": "GCF_000001405.38", "assembly_status": "current"}, {"assembly": "GRCh37", "chr": "8", "accession": "NC_000008.10", "start": 87586162, "stop": 87755902, "display_start": 87586162, "display_stop": 87755902, "strand": "-", "variant_length": 169741, "assembly_accession_version": "GCF_000001405.25", "assembly_status": "previous"}], "xrefs": [{"db": "Gene", "id": "54714"}, {"db": "OMIM", "id": "605080", "type": "MIM"}, {"db": "HGNC", "id": "HGNC:2153"}]}], "citations": [{"ids": [{"source": "PubMed", "value": "28795510"}], "type": "general"}], "id": 424200}], "names": [{"value": {"type": "Preferred", "value": "NC_000008.11:g.86688947_86688948ins[MF045863.1:g.1_36978]"}}], "id": 430672}, "traits": {"type": "Disease", "traits": [{"type": "Disease", "names": [{"value": {"type": "Preferred", "value": "Achromatopsia 3"}, "xrefs": [{"db": "Genetic Alliance", "id": "Achromatopsia+3/117"}, {"db": "MONDO", "id": "MONDO:0009875"}]}, {"value": {"type": "Alternate", "value": "ROD MONOCHROMACY 1"}, "xrefs": [{"db": "OMIM", "id": "262300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "ROD MONOCHROMATISM 1"}, "xrefs": [{"db": "OMIM", "id": "262300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "Pingelapese blindness"}}, {"value": {"type": "Alternate", "value": "Achromatopsia with myopia"}}, {"value": {"type": "Alternate", "value": "Total colorblindness with myopia"}}, {"value": {"type": "Alternate", "value": "ACHM1 (formerly)"}}, {"value": {"type": "Alternate", "value": "Rod monochromatism 1 (formerly)"}}, {"value": {"type": "Alternate", "value": "Rod monochromacy 1 (formerly)"}}, {"value": {"type": "Alternate", "value": "RMCH1 (formerly)"}}], "symbols": [{"value": {"type": "Preferred", "value": "ACHM3"}, "xrefs": [{"db": "OMIM", "id": "262300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "ACHM1"}, "xrefs": [{"db": "OMIM", "id": "262300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "RMCH1"}, "xrefs": [{"db": "OMIM", "id": "262300", "type": "MIM"}]}, {"value": {"type": "Alternate", "value": "CNGB3"}}], "attributes": [{"value": {"type": "public definition", "value": "Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. All individuals with achromatopsia (achromats) have impaired color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). Most individuals have complete achromatopsia, with total lack of function of all three types of cones. Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning. The manifestations are similar to those of individuals with complete achromatopsia, but generally less severe. Hyperopia is common in achromatopsia. Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time; both nystagmus and sensitivity to bright light may improve slightly. Although the fundus is usually normal, macular changes (which may show early signs of progression) and vessel narrowing may be present in some affected individuals. 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"measures": [{"type": "variation", "attributes": [{"type": "HGVS", "value": "NC_000008.11:g.86688947_86688948insMF045863.1g.1_36978"}], "measure_relationship": [{"type": "variant in gene", "symbols": [{"value": {"type": "Preferred", "value": "CNGB3"}}]}]}]}, "traits": {"type": "Disease", "traits": [{"names": [{"value": {"type": "Preferred", "value": "ACHM3"}}]}]}, "citations": [{"ids": [{"source": "PubMed", "value": "28795510"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": "28795510"}], "type": "general"}], "comments": [{"text": "Tandem duplication of exons 4-7"}]}]} +{"reference_clinvar_assertion": {"clinvar_accession": {"acc": "RCV000497553", "version": 1, "type": "RCV", "date_updated": "2023-06-17", "date_created": "2017-08-20"}, "record_status": "current", "clinical_significance": {"review_status": "no assertion criteria provided", "description": "pathogenic", "date_last_evaluated": "2017-03-27"}, "assertion": "variation to disease", "observed_in": [{"sample": 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All individuals with achromatopsia (achromats) have impaired color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). Most individuals have complete achromatopsia, with total lack of function of all three types of cones. Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning. The manifestations are similar to those of individuals with complete achromatopsia, but generally less severe. Hyperopia is common in achromatopsia. Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. 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"date_created": "2016-11-13", "date_last_updated": "2023-09-09", "id": 628062}, "record_status": "current", "title": "46;XY;t(12;14)(q15;q13)mat AND multiple conditions", "clinvar_assertions": [{"id": 627922, "submission_id": {"local_key": "DGAP296|HPO:HP:0003251;HP:0000027;HP:0000798;HP:0012871;HP:0010877;HP:0010862;HP:0000505;HP:0007018;HP:0000750;HP:0002381;HP:0001999;HP:0000324;HP:0000582;HP:0008551;HP:0001159", "submitter": "Talkowski Laboratory, Center for Human Genetic Research, Massachusetts General Hospital", "submitted_assembly": "GRCh37", "submitter_date": "2016-09-23"}, "clinvar_accession": {"acc": "SCV000320883", "version": 1, "type": "SCV", "date_updated": "2016-11-13", "date_created": "2016-11-13", "org_id": "505929", "org_type": "primary", "org_category": "laboratory"}, "assertion_type": "variation to disease", "record_status": "current", "clinical_significance": [{"review_status": "criteria provided, single submitter", "descriptions": ["uncertain significance"], "citations": [{"ids": [{"source": "PubMed", "value": "27841880"}], "type": "general"}], "date_last_evaluated": "2016-08-20"}], "external_ids": [{"db": "Talkowski Laboratory, Center for Human Genetic Research", "id": "DGAP296"}], "attributes": [{"attribute": {"type": "AssertionMethod", "value": "Talkowski Lab Assertion Criteria for BCA 2016"}, "citations": [{"type": "general", "url": "https://submit.ncbi.nlm.nih.gov/ft/byid/x90lyabz/talkowski_lab_assertion_criteria_for_bca_2016.pdf", "citation_text": "Talkowski_Lab_Assertion_Criteria_for_BCA_2016.pdf"}]}], "observed_in": [{"sample": {"origin": "maternal", "species": {"value": "human", "taxonomy_id": 9606}, "affected_status": "yes", "gender": "male", "family_data": {"family_history": "yes"}}, "methods": ["research"], "observed_data": [{"attribute": {"type": "Description", "value": "not provided"}}], "comments": [{"text": "Translocation segregates with eye anomaly in the family", "type": "public"}]}], "measures": {"type": "Variant", "measures": [{"type": "translocation", "names": [{"value": {"type": "Preferred", "value": "46;XY;t(12;14)(q15;q13)mat"}}]}]}, "traits": {"type": "Finding", "traits": [{"xrefs": [{"db": "HP", "id": "HP:0003251"}]}, {"xrefs": [{"db": "HP", "id": "HP:0000027"}]}, {"xrefs": [{"db": "HP", "id": "HP:0000798"}]}, {"xrefs": [{"db": "HP", "id": "HP:0012871"}]}, {"xrefs": [{"db": "HP", "id": "HP:0010877"}]}, {"xrefs": [{"db": "HP", "id": "HP:0010862"}]}, {"xrefs": [{"db": "HP", "id": "HP:0000505"}]}, {"xrefs": [{"db": "HP", "id": "HP:0007018"}]}, {"xrefs": [{"db": "HP", "id": "HP:0000750"}]}, {"xrefs": [{"db": "HP", "id": "HP:0002381"}]}, {"xrefs": [{"db": "HP", "id": "HP:0001999"}]}, {"xrefs": [{"db": "HP", "id": "HP:0000324"}]}, {"xrefs": [{"db": "HP", "id": "HP:0000582"}]}, {"xrefs": [{"db": "HP", "id": "HP:0008551"}]}, {"xrefs": [{"db": "HP", "id": "HP:0001159"}]}]}, "citations": [{"ids": [{"source": "PubMed", "value": "27841880"}], "type": "general"}, {"ids": [{"source": "PubMed", "value": 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"vardbs/GRCh37/strucvars/clinvar.tsv:2023-02-06", - "dc:title": "ClinVar Structural Variants (2023-02-06)", - "dc:description": "This TSV file contains the structural variants from ClinVar with their pathogenicity assertions (2022-08-12)", - "dc:created": "2023-02-06", - "dc:creator": "NCBI ClinVar", - "dc:contributor": [ - "VarFish Developer Team" - ], - "dc:source": [ - "PMID:31777943", - "https://www.ncbi.nlm.nih.gov/clinvar/" - ], - "tsv:columns": { - "chromosome": "Chromosome name without chr prefix", - "start": "1-based start position", - "end": "1-based end position", - "variation_type": "SV type", - "vcv": "ClinVar VCV identifier", - "pathogenicity": "ClinVar pathogenicity assertion" - } -}