ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2264G>T (p.Gly755Val)

gnomAD frequency: 0.00018  dbSNP: rs367990772
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000644638 SCV000766341 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 755 of the DSC2 protein (p.Gly755Val). This variant is present in population databases (rs367990772, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of DSC2-related conditions (PMID: 32009526). ClinVar contains an entry for this variant (Variation ID: 536270). 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.
Color Diagnostics, LLC DBA Color Health RCV001185027 SCV001351156 likely benign Cardiomyopathy 2020-09-09 criteria provided, single submitter clinical testing
GeneDx RCV001547044 SCV001766663 uncertain significance not provided 2020-10-23 criteria provided, single submitter clinical testing Reported in an individual with cardiomyopathy who underwent exome analysis (Pottinger et al., 2020); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 536270; Landrum et al., 2016); 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: 32009526)
Ambry Genetics RCV002449035 SCV002733877 likely benign Cardiovascular phenotype 2021-09-02 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.

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