Submissions for variant NM_001943.5(DSG2):c.2710C>G (p.Gln904Glu)

gnomAD frequency: 0.00001  dbSNP: rs372335085

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001070844	SCV001236118	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 904 of the DSG2 protein (p.Gln904Glu). This variant is present in population databases (rs372335085, gnomAD 0.002%). 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: 863793). 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. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001092839	SCV001249537	uncertain significance	not provided	2020-05-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184354	SCV001350316	uncertain significance	Cardiomyopathy	2023-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 904 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 1/249024 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.
All of Us Research Program, National Institutes of Health	RCV004000194	SCV004821830	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-10-06	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces glutamine with glutamic acid at codon 904 of the DSG2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/245680 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.