ClinVar Genomic variation as it relates to human health

Variant summary: DSG2 c.6G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0051 in 45050 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 500 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.6G>A has been reported in the literature in an individual affected with Arrhythmia (Lahtinen 2011). This report however does not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrence with another pathogenic variant have been found in our internal database (KCNH2 c.1841C>T, p.Ala614Val), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (three of them calling it 'likely benign' and one classifying it as a 'VUS') without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.

Ala2Ala in exon 1 of DSG2: This variant is not expected to have clinical signifi cance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.2% (14/7372) of Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS). Ala2Ala in exon 1 of DSG2 (allele fr equency = 0.2%, 14/7372) **

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is 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.

DSG2: BP4, BP7

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).