Submissions for variant NM_001943.5(DSG2):c.2079A>C (p.Glu693Asp)

gnomAD frequency: 0.00003  dbSNP: rs375595872

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691323	SCV000819099	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 693 of the DSG2 protein (p.Glu693Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 570467). 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.
Color Diagnostics, LLC DBA Color Health	RCV001186672	SCV001353212	uncertain significance	Cardiomyopathy	2024-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 693 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 DSG2-related disorders in the literature. 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	RCV002422497	SCV002726795	uncertain significance	Cardiovascular phenotype	2025-01-07	criteria provided, single submitter	clinical testing	The c.2079A>C (p.E693D) alteration is located in exon 14 (coding exon 14) of the DSG2 gene. This alteration results from a A to C substitution at nucleotide position 2079, causing the glutamic acid (E) at amino acid position 693 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003999556	SCV004821751	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 693 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 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV004792382	SCV005408604	uncertain significance	not provided	2024-07-16	criteria provided, single submitter	clinical testing	BP4
PreventionGenetics, part of Exact Sciences	RCV004754531	SCV005364142	uncertain significance	DSG2-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The DSG2 c.2079A>C variant is predicted to result in the amino acid substitution p.Glu693Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% 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.