ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1063G>A (p.Ala355Thr)

gnomAD frequency: 0.00004  dbSNP: rs201046640
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171900 SCV000050904 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Blueprint Genetics RCV000208226 SCV000263852 uncertain significance Cardiac arrest 2015-11-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621568 SCV000737809 likely benign Cardiovascular phenotype 2016-11-29 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina RCV001124514 SCV001283483 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health RCV001181081 SCV001346157 likely benign Cardiomyopathy 2019-02-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001124514 SCV001416619 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2023-12-03 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 355 of the DSG2 protein (p.Ala355Thr). This variant is present in population databases (rs201046640, gnomAD 0.1%). 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: 191629). 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 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.
GeneDx RCV000171900 SCV001771150 uncertain significance not provided 2023-02-22 criteria provided, single submitter clinical testing Reported in a cohort not selected for arrhythmia, cardiomyopathy or family history of sudden death who underwent exome anaylsis (Ng et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362)
All of Us Research Program, National Institutes of Health RCV004806159 SCV005428695 likely benign Arrhythmogenic right ventricular cardiomyopathy 2024-09-27 criteria provided, single submitter clinical testing

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