ClinVar Genomic variation as it relates to human health

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).

Variant summary: VCL c.590C>T (p.Thr197Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 1614138 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05). c.590C>T has been reported in the literature in individuals affected with Cardiomyopathy without strong evidence for causality (examples: Kuhnisch_2019, Lint_2019) . These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31568572, 30847666). ClinVar contains an entry for this variant (Variation ID: 45617). Based on the evidence outlined above, the variant was classified as likely benign.

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.

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.

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).