Submissions for variant NM_001943.5(DSG2):c.3040G>A (p.Val1014Ile)

gnomAD frequency: 0.00003  dbSNP: rs200830807

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171834	SCV000050859	uncertain significance	Primary dilated cardiomyopathy	2018-04-05	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037296	SCV000060953	uncertain significance	not specified	2012-07-30	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000590405	SCV000233514	likely benign	not provided	2018-04-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 27532257, 27114410, 20716751, 24503780, 28600387, 27527004)
Ambry Genetics	RCV000242473	SCV000320151	uncertain significance	Cardiovascular phenotype	2023-05-22	criteria provided, single submitter	clinical testing	The p.V1014I variant (also known as c.3040G>A), located in coding exon 15 of the DSG2 gene, results from a G to A substitution at nucleotide position 3040. The valine at codon 1014 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in both dilated cardiomyopathy and hypertrophic cardiomyopathy cohorts; however, clinical details were limited (Elliott P, Circ Cardiovasc Genet 2010 Aug; 3(4):314-22; Pugh TJ et al. Genet. Med. 2014 Aug; 16(8):601-8; Lopes LR et al. Heart. 2015;101(4):294-301; Walsh R et al. Genet. Med., 2017 02;19:192-203). In a cohort of exertion-related sudden unexplained death in the young, this variant was detected in one individual who was also heterozygous for a disease-causing variant in MYBPC3 (Anderson JH et al. Circ Cardiovasc Genet, 2016 Jun;9:259-65). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence for this variant is limited at this time, its clinical significance is unclear.
Invitae	RCV000473314	SCV000551018	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-01-22	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037296	SCV000697887	uncertain significance	not specified	2022-04-10	criteria provided, single submitter	clinical testing	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769519	SCV000900914	uncertain significance	Cardiomyopathy	2015-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769519	SCV000911597	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	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.