Submissions for variant NM_001943.5(DSG2):c.1154G>A (p.Gly385Asp)

gnomAD frequency: 0.00001  dbSNP: rs727504748

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156048	SCV000205761	uncertain significance	not specified	2013-09-27	criteria provided, single submitter	clinical testing	The Gly385Asp variant in DSG2 has not been reported in individuals with cardiomy opathy or in large population studies. Computational analysis (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly385Asp variant may impact the protein, though this information is not predic tive enough to determine pathogenicity. Additional information is needed to full y assess the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV001189968	SCV001357369	uncertain significance	Cardiomyopathy	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 385 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850146	SCV002306596	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2021-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with aspartic acid at codon 385 of the DSG2 protein (p.Gly385Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). 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: 179261). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	RCV003998299	SCV004819514	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 385 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV005229994	SCV005875459	uncertain significance	not provided	2024-05-30	criteria provided, single submitter	clinical testing	The DSG2 c.1154G>A; p.Gly385Asp variant (rs727504748), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 179261). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.46). Due to limited information, the clinical significance of this variant is uncertain at this time.