Submissions for variant NM_014000.3(VCL):c.590C>T (p.Thr197Ile)

gnomAD frequency: 0.00019  dbSNP: rs189242810

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000154123	SCV000051354	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038835	SCV000062513	uncertain significance	not specified	2010-07-16	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000154123	SCV000203786	uncertain significance	not provided	2014-02-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000154123	SCV000236483	uncertain significance	not provided	2017-06-02	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the VCL gene. The T197I variant has been previously reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013); however, a follow-up cardiac evaluation was not reported. The T197I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant is observed in 13/11,572 (0.11%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, the T197I variant is also classified as a variant of uncertain significance by other clinical laboratories in ClinVar (SCV000062513.4, SCV000203786.3, SCV000318974.1, SCV000280564.1; Landrum et al., 2016).
Ambry Genetics	RCV000252580	SCV000318974	likely benign	Cardiovascular phenotype	2022-03-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084501	SCV000645870	likely benign	Dilated cardiomyopathy 1W	2024-01-19	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000038835	SCV000740396	uncertain significance	not specified	2017-01-27	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852615	SCV000995318	likely benign	Cardiomyopathy	2019-03-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000852615	SCV001333587	uncertain significance	Cardiomyopathy	2017-12-01	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000038835	SCV000280564	uncertain significance	not specified	2013-04-22	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. VCL p.Thr197Ile (c.590C>T) This variant has not been reported in conjunction with disease. This variant is located in coding exon 5 of the VCL gene. The threonine at codon 197 is replaced by isoleucine, an amino acid with some similar properties. In silico analysis with PolyPhen-2 predicts the variant to be benign and tolerated by SIFT. Mutation taster predicts this variant to be disease-causing, probably due to the fact that Threonine is well conserved. The Threonine at codon 197 is conserved across species, as are neighboring amino acids. In total the variant has been seen in 4/7,595 individuals from publicly available population datasets. The variant was previously reported in the SNP database (rs189242810). This variant is seen in 3/8600 European American alleles and 0/4406 African American alleles listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/20/13). Note that this dataset does not match the patient's ancestry (Mexican). This is a frequency of approximately 0.02% (3/13006). 1000 genomes data reports the T-allele in 1/2184 chromosomes for a frequency of 0.05%. The highest observed frequency was 0.76% (1/132) Mexican-American chromosomes studied. Please note, the patient's ancestry is Mexican.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000154123	SCV001977885	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000154123	SCV001979547	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952439	SCV004770499	likely benign	VCL-related disorder	2022-10-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).