ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 23861362, 25016126, 25351510, 26656175, 23396983, 24503780, 20474083, 27930701)

p.His636Arg in exon 14 of VCL: This variant is not expected to have clinical sig nificance because it has been identified in 0.67% (44/6604) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs71579374).

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Variant summary: VCL c.1907A>G (p.His636Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 252006 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 31 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is benign. c.1907A>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Zimmerman_2010). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. At least one co-occurrence with a pathogenic variant has been reported (MYBPC3 c.1090+1G>A, LOVD database citing Lopes_2013), providing supporting evidence for a benign role.Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x benign, 2x likely benign, 1x VUS). Based on the evidence outlined above, the variant was classified as 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.

VCL: BS1, BS2

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).