ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2434G>T (p.Gly812Cys) (rs121913010)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195104 SCV000060943 uncertain significance not specified 2019-09-03 criteria provided, single submitter clinical testing The p.Gly812Cys variant in DSG2 has been identified in at least 2 individuals with ARVC (Awad 2006, Ambry pers. comm., LMM data). It has also been identified in 0.003% (3/113164) of European chromosomes by gnomAD ( Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In contrast, in vitro functional studies do not provide strong support for or against an impact to the protein (Gehmlich 2010). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_Supporting.
Ambry Genetics RCV000618751 SCV000737925 likely pathogenic Cardiovascular phenotype 2018-07-09 criteria provided, single submitter clinical testing The p.G812C variant (also known as c.2434G>T), located in coding exon 15 of the DSG2 gene, results from a G to T substitution at nucleotide position 2434. The glycine at codon 812 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple probands with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Awad MM et al. Am. J. Hum. Genet., 2006 Jul;79:136-42; Ambry internal data). Functional studies in vitro have demonstrated normal desmoglein-2 subcellular localization, protein-protein interactions, and cardiomyocyte cohesion; however, the mechanism by which alterations in DSG2 contribute to disease is not completely understood (Gehmlich K et al. Heart Rhythm, 2010 Oct;7:1446-53; Schlipp A et al. Cardiovasc. Res., 2014 Nov;104:245-57). Another alteration affecting this amino acid (p.G812S, c.2434G>A) has been identified in a proband with ARVC and has been reported to co-segregate with disease (Gehmlich K et al. Heart Rhythm, 2010 Oct;7:1446-53). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000018307 SCV001214221 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 812 of the DSG2 protein (p.Gly812Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs121913010, ExAC 0.003%). This variant has been observed in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16773573). This variant is also known as 2431G>T, G811C in the literature. ClinVar contains an entry for this variant (Variation ID: 16814). This variant has been reported to have conflicting or insufficient data to determine the effect on DSG2 protein function while some aspects of DSG2 function appear to be preserved (PMID: 20708101, 25213555). 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.
Color Health, Inc RCV001183802 SCV001349629 uncertain significance Cardiomyopathy 2020-03-25 criteria provided, single submitter clinical testing
OMIM RCV000018307 SCV000038586 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2006-07-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000037286 SCV000190171 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 no assertion criteria provided research

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