ClinVar Genomic variation as it relates to human health

p.Leu732Val in exon 14 of DSC2: This variant been reported in 4 individuals with ARVC and 1 individual DCM and absent from 700 control chromosomes (Bhuiyan 2009 , Cox 2011, Garcia-Pavia 2011, Quarta 2011). However, it has been identified in 0.2% (134/66698) of European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs151024019). In addition, Leucine (Le u) at position 732 is not conserved in evolution and the variant is present in f our mammals, suggesting that a change to this position may be tolerated. In summ ary, this variant is likely benign but a modifying role cannot be excluded.

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.

This variant is associated with the following publications: (PMID: 21606390, 21606396, 23299917, 20031616, 21859740, 24055113, 23861362, 23396983, 24967631, 25447171, 21636032, 26899768, 26332594)

Low GERP score may suggest that this variant may belong in a lower pathogenicity class

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.

DSC2: BP4, 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).

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. Given presence in controls and somewhat weak case data (reviewed below) we consider this variant to be of uncertain significance. This variant has been reported in association with ARVC in the literature, although the clinical significance of this variant is unclear. It has been reported in 4 individuals with ARVC and 1 individual with DCM (Bhuiyan 2009; Cox 2011; Garcia-Pavia 2011; Quarta 2011). In these studies it was absent from 350 total control individuals. However, it has also been identified in 0.13% of European American chromosomes in the NHLBI ESP dataset. Bhuiyan et al. 2009 reported this variant in one individual with ARVC who also harbored another missense variant in the DSG2 gene, and both individuals were absent from 150 ethnically matched control individuals. Cox et al. 2011 reported this variant as an unclassified variant after observing it in two patients with ARVC who also harbored additional pathogenic variants or novel variants. This variant commonly occurs together with the DSG2 Val392Ile variant, which is also likely benign, suggesting that these variants are present on the same allele. This is a conservative amino acid change where a nonpolar leucine residue is exchanged for a nonpolar valine residue. The leucine at codon 732 is not well conserved across mammalian species. In silico analysis consistently predicts this variant to be benign (PolyPhen predicts this variant to be probably benign mutation taster predicts this variant to be a polymorphism). In total this variant has been seen in 14 out of ~6850 control individuals from the literature and publicly available population datasets. It is present in 14 total individuals of approximately 6500 individuals of European American and African American ancestry in the NHLBI Exome Sequencing Project dataset, for an allele frequency of .11%. This variant is present in dbSNP as rs151024019, submitted by ESP and 1000Genomes. It is also present at low frequency in 1000Genomes (allele frequency of .05%). Finally, this variant is present in the ExAC database in 146/ 61,434 individuals of varying ancestries (as of December 7, 2014). Presence of a variant among individuals in the general population cannot definitively rule it out as the cause of disease, as even gold-standard pathogenic cardiomyopathy variants have been found in population datasets (Pan et al. 2012).