ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2446G>A (p.Val816Met)

gnomAD frequency: 0.00001  dbSNP: rs377700521
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000039424 SCV000063108 uncertain significance not specified 2012-04-11 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Val816Met varia nt (DSC2) has not been reported in the literature nor previously identified by o ur laboratory. Computational analyses (biochemical amino acid properties, conser vation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Val816Met variant may n ot impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional studies are needed to fully assess its clinical si gnificance.
Illumina Laboratory Services, Illumina RCV000408189 SCV000408092 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2018-01-12 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 RCV000408189 SCV001412686 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2023-10-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 816 of the DSC2 protein (p.Val816Met). This variant is present in population databases (rs377700521, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy or arrhythmia (PMID: 27532257, 31484862). ClinVar contains an entry for this variant (Variation ID: 46181). 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 DSC2 protein function with a negative predictive value of 80%. 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.
PreventionGenetics, part of Exact Sciences RCV003894867 SCV004708315 uncertain significance DSC2-related disorder 2023-11-11 criteria provided, single submitter clinical testing The DSC2 c.2446G>A variant is predicted to result in the amino acid substitution p.Val816Met. This variant was reported in individuals with dilated cardiomyopathy (Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). This variant has also been reported in a patient with arrhythmia and in his unaffected father (Chen et al. 2019. PubMed ID: 31484862). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-28648922-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health RCV003996439 SCV004830276 uncertain significance Familial isolated arrhythmogenic right ventricular dysplasia 2023-06-28 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.