ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1481A>C (p.Asp494Ala)

gnomAD frequency: 0.00003  dbSNP: rs193298428
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001379311 SCV001577095 likely pathogenic Arrhythmogenic right ventricular dysplasia 10 2023-05-11 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. ClinVar contains an entry for this variant (Variation ID: 199808). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 23514727, 29178656). This variant is present in population databases (rs193298428, gnomAD 0.03%). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 494 of the DSG2 protein (p.Asp494Ala).
Ambry Genetics RCV002390449 SCV002698853 likely benign Cardiovascular phenotype 2022-01-19 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003486735 SCV004240499 uncertain significance Cardiomyopathy 2023-03-22 criteria provided, single submitter clinical testing

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