ClinVar Genomic variation as it relates to human health

The Val1014Ile variant in DSG2 has been reported in 1 individual with DCM and wa s absent from 400 control chromosomes (Elliott 2010). In addition, this variant has been identified in 3/8352 European American chromosomes from a broad populat ion by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). C omputational analyses (biochemical amino acid properties, conservation, AlignGVG D, PolyPhen2, and SIFT) do not provide strong support for or against an impact t o the protein. Additional information is needed to fully assess the clinical sig nificance of the Val1014Ile variant.

Variant summary: DSG2 c.3040G>A (p.Val1014Ile) results in a 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 7.2e-05 in 249792 control chromosomes. The observed variant frequency is approximately 7.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 (1e-05), strongly suggesting that the variant is benign. c.3040G>A has been reported in the literature as a VUS in settings of multigene panel testing of individuals with a variety of cardiac phenotypes such as idiopathic dilated cardiomyopathy (DCM), DCM, exertion-related sudden unexplained death in the young (SUDY) (example, Elliott_2010, Pugh_2014, Anderson_2016, Mellor_2017, Walsh_2017) and as a Likely Pathogenic cardiomyopathy associated variant in at-least one individual with hypertension/stroke (example, Ng_2013). These data do not allow any conclusion about variant significance. At-least one of these reports mentions a co-occurrence with another pathogenic variant in an individual with exertion-related sudden unexplained death in the young (SUDY) (MYBPC3 c.2374T>C, p.Trp792Arg), providing supporting evidence for a benign role (Anderson_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Likely benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1014 of the DSG2 protein (p.Val1014Ile). This variant is present in population databases (rs200830807, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 20716751, 23861362, 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 44309). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces valine with isoleucine at codon 1014 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been identified in three individuals affected with dilated cardiomyopathy (PMID: 20716751, 23861362, 24503780). This variant has been observed in a young individual with exertion-induced sudden unexplained death, who also carried a pathogenic variant in the MYBPC3 gene (PMID: 27114410). This variant has also been identified in 19/280798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The c.3040G>A (p.V1014I) alteration is located in exon 15 (coding exon 15) of the DSG2 gene. This alteration results from a G to A substitution at nucleotide position 3040, causing the valine (V) at amino acid position 1014 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

See Variant Classification Assertion Criteria.