ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1562A>G (p.Asp521Gly) (rs730880077)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000539173 SCV000641964 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2017-07-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 521 of the DSG2 protein (p.Asp521Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs730880077, ExAC 0.02%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 180320). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000157185 SCV001156268 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2017-03-16 criteria provided, single submitter research The DSG2 Asp521Gly is absent in the 1000 genomes project (http://www.1000genomes.org/), and present at low frequency in the Exome Aggregation Consortium dataset (MAF=0.000025; http://exac.broadinstitute.org/). We identified this variant in a HCM patient with no family history of disease or SCD. Computational tools SIFT, MutationTaster, and PolyPhen-2 predict the variant to have a deleterious effect. In summary, while this is a rare variant, there is currently no evidence that DSG2 can cause an HCM phenotype, therefore we classify DSG2 Asp521Gly as a variant of "uncertain significance".
Illumina Clinical Services Laboratory,Illumina RCV000539173 SCV001286953 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 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.
Color Health, Inc RCV001181773 SCV001346995 uncertain significance Cardiomyopathy 2018-11-11 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157185 SCV000206909 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-10-14 no assertion criteria provided clinical testing

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