Submissions for variant NM_001943.5(DSG2):c.2165G>A (p.Arg722Lys)

gnomAD frequency: 0.00002  dbSNP: rs376819371

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484089	SCV000572052	uncertain significance	not provided	2019-09-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 422554; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Color Diagnostics, LLC DBA Color Health	RCV000772021	SCV000904977	uncertain significance	Cardiomyopathy	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 722 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/249456 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001366209	SCV001562505	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 722 of the DSG2 protein (p.Arg722Lys). This variant is present in population databases (rs376819371, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422554). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. 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	RCV004003379	SCV004821760	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 722 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/249456 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.