Submissions for variant NM_001943.5(DSG2):c.2405A>G (p.Glu802Gly)

gnomAD frequency: 0.00004  dbSNP: rs763315024

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000546510	SCV000408249	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000546510	SCV000641973	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 802 of the DSG2 protein (p.Glu802Gly). This variant is present in population databases (rs763315024, gnomAD 0.005%). 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: 326485). 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.
Color Diagnostics, LLC DBA Color Health	RCV000777772	SCV000913743	uncertain significance	Cardiomyopathy	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 802 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 7/249468 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777772	SCV002043140	uncertain significance	Cardiomyopathy	2019-09-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002450888	SCV002738559	uncertain significance	Cardiovascular phenotype	2020-12-11	criteria provided, single submitter	clinical testing	The p.E802G variant (also known as c.2405A>G), located in coding exon 15 of the DSG2 gene, results from an A to G substitution at nucleotide position 2405. The glutamic acid at codon 802 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.