ClinVar Miner

Submissions for variant NM_014000.3(VCL):c.590C>T (p.Thr197Ile) (rs189242810)

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Total submissions: 10
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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,Partners HealthCare Personalized Medicine RCV000038835 SCV000062513 uncertain significance not specified 2010-07-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 uncertain significance Cardiovascular phenotype 2019-08-14 criteria provided, single submitter clinical testing The p.T197I variant (also known as c.590C>T), located in coding exon 5 of the VCL gene, results from a C to T substitution at nucleotide position 590. The threonine at codon 197 is replaced by isoleucine, an amino acid with similar properties. This variant has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart. 2015;101(4):294-301). This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV001084501 SCV000645870 likely benign Dilated cardiomyopathy 1W 2020-11-19 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.

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