Submissions for variant NM_001943.5(DSG2):c.2033G>C (p.Gly678Ala)

gnomAD frequency: 0.00006  dbSNP: rs372494397

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154704	SCV000204383	uncertain significance	not specified	2013-07-31	criteria provided, single submitter	clinical testing	The Gly678Ala variant in DSG2 has not been reported in individuals with cardiomy opathy but has been identified in 1/4012 African American chromosomes by the NHL BI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Computational a nalyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly678Ala variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional information is needed to fully assess the clinical significance of the Gly678Ala variant.
Invitae	RCV000701131	SCV000829915	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 678 of the DSG2 protein (p.Gly678Ala). This variant is present in population databases (rs372494397, gnomAD 0.008%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic cardiomyopathy (HCM) (PMID: 24070718, 26656175). ClinVar contains an entry for this variant (Variation ID: 178021). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769512	SCV000900907	uncertain significance	Cardiomyopathy	2016-05-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769512	SCV001342476	uncertain significance	Cardiomyopathy	2022-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 678 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with arrhythmogenic cardiomyopathy (PMID 24070718, 32102357), in an individual affected with hypertrophic cardiomyopathy (PMID: 26656175), and in an individual affected with dilated cardiomyopathy and ventricular tachycardia (PMID: 33552729). This variant has also been identified in 13/280686 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.
Ambry Genetics	RCV002415655	SCV002722997	uncertain significance	Cardiovascular phenotype	2022-08-12	criteria provided, single submitter	clinical testing	The p.G678A variant (also known as c.2033G>C), located in coding exon 14 of the DSG2 gene, results from a G to C substitution at nucleotide position 2033. The glycine at codon 678 is replaced by alanine, an amino acid with similar properties. This alteration has been previously reported in an arrhythmogenic right ventricular cardiomyopathy cohort, in a hypertrophic cardiomyopathy cohort, and in an individual with nondystrophic myotonia and drug-induced Brugada Syndrome (Rigato I et al. Circ Cardiovasc Genet. 2013;6:533-42; Bottillo I et al. Gene. 2016;577:227-35; Cavalli M et al. Front Neurol. 2018;9:385). This amino acid position is poorly conserved in available vertebrate species, and alanine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483341	SCV002788659	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-07-26	criteria provided, single submitter	clinical testing
GeneDx	RCV003105800	SCV003761808	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26138720, 34426522, 26656175, 24070718, 32102357, 29899727)