Submissions for variant NM_001943.5(DSG2):c.2944G>A (p.Glu982Lys)

dbSNP: rs781744343

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001805715	SCV002051889	uncertain significance	Cardiomyopathy	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 982 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 reported in an individual affected with dilated cardiomyopathy as well as in a healthy individual (PMID: 31983221). This variant has not been identified 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	RCV002440887	SCV002752475	uncertain significance	Cardiovascular phenotype	2021-12-23	criteria provided, single submitter	clinical testing	The p.E982K variant (also known as c.2944G>A), located in coding exon 15 of the DSG2 gene, results from a G to A substitution at nucleotide position 2944. The glutamic acid at codon 982 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003517351	SCV004368606	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 982 of the DSG2 protein (p.Glu982Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 1332669). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
All of Us Research Program, National Institutes of Health	RCV004009156	SCV004821856	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 982 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 reported in an individual affected with dilated cardiomyopathy as well as in a healthy individual (PMID: 31983221). This variant has not been identified 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.
Clinical Genomics Laboratory, Stanford Medicine	RCV003517351	SCV005062014	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2021-07-26	criteria provided, single submitter	clinical testing	The p.Glu982Lys variant in the DSG2gene has not been previously reported in association with disease. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The glutamic acid at position 982 is not evolutionarily conserved and 3 vertebrate species have a lysine at this position. Computational tools predict that the p.Glu982Lys variant does not impact protein function; however, the accuracy of in silicoalgorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of thep.Glu982Lysvariant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; BP4]