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

dbSNP: rs121913010

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002223761	SCV000060943	uncertain significance	not provided	2023-01-20	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 (http://gnomad.broadinstitute.org). 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 dysplasia 10	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 812 of the DSG2 protein (p.Gly812Cys). This variant is present in population databases (rs121913010, gnomAD 0.003%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 16773573). This variant is also known as 2431G>T, G811C. ClinVar contains an entry for this variant (Variation ID: 16814). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DSG2 function (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 Diagnostics, LLC DBA Color Health	RCV001183802	SCV001349629	uncertain significance	Cardiomyopathy	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 812 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not affect membrane expression of the mutant protein and does not affect cardiomyocyte cohesion in vitro (PMID: 25213555). This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 16773573, 20031617), in an individual affected with probable ARVC (PMID: 20857253) and in an individual affected with exercise-induced ARVC (PMID: 23871885). This variant has been identified in 3/249442 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223761	SCV002503132	uncertain significance	not provided	2021-12-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914852	SCV004730158	uncertain significance	DSG2-related disorder	2023-12-18	criteria provided, single submitter	clinical testing	The DSG2 c.2434G>T variant is predicted to result in the amino acid substitution p.Gly812Cys. This variant has been reported in two individuals diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) (reported as p.Gly811Cys in Table 1, Awad et al. 2006. PubMed ID: 16773573; Tan et al. 2010. PubMed ID: 20857253). It was also been observed in an individual with suspected ARVC (den Haan et al. 2009. PubMed ID: 20031617) and another individual who experienced ARVC symptoms following strenuous exercise (Table S1, James et al. 2013. PubMed ID: 23871885). In vitro studies using rat cardiomyocytes found p.Gly812Cys-DSG2 had normal protein expression and cell membrane localization (Gehmlich et al. 2010. PubMed ID: 20708101). Additional experiments (same study) demonstrated this variant does not apparently alter plakoglobin binding affinity but were inconclusive regarding its effect on plakophilin-2 binding. Another study performed a cell fragmentation assay using mouse cardiomyocytes and found that the p.Gly812Cys variant did not significantly alter cell-cell adhesion relative to wild type (Schlipp et al. 2014. PubMed ID: 25213555). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000037286	SCV004821798	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 812 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant does not affect membrane expression of the mutant protein and does not affect cardiomyocyte cohesion in vitro (PMID: 25213555). This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 16773573, 20031617), in an individual affected with probable ARVC (PMID: 20857253) and in an individual affected with exercise-induced ARVC (PMID: 23871885). This variant has been identified in 3/249442 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.
OMIM	RCV000018307	SCV000038586	pathogenic	Arrhythmogenic right ventricular dysplasia 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