ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1048G>T (p.Asp350Tyr)

gnomAD frequency: 0.00003  dbSNP: rs766413086
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000222161 SCV000271703 uncertain significance not specified 2015-03-04 criteria provided, single submitter clinical testing The p.Asp350Tyr variant in DSC2 has been reported in 1 Caucasian adult with prob able ARVC (diagnosed upon myocardial biopsy) as well as two siblings with abnorm al ECGs (Bhuiyan 2009). This variant has also been identified in 1/10436 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org). Computational prediction tools and conservation analysis suggest that i t may impact the protein, though this information is not predictive enough to de termine pathogenicity. In summary, the clinical significance of the p.Asp350Tyr variant is uncertain.
Color Diagnostics, LLC DBA Color Health RCV001524245 SCV001734040 uncertain significance Cardiomyopathy 2020-09-15 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with tyrosine at codon 350 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with probably arrhythmogenic right ventricular cardiomyopathy as well as two siblings with abnormal ECGs (PMID: 20031616). This variant has also been reported in an individual without a diagnosis of arrhythmogenic right ventricular cardiomyopathy (PMID: 28471438). This variant has been identified in 2/282446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx RCV001753642 SCV001985377 uncertain significance not provided 2019-08-15 criteria provided, single submitter clinical testing Reported in one female with a probable diagnosis of ARVC per task force criteria in published literature (Bhuiyan et al., 2009); this variant was also found in her two siblings with positive findings on signal-averaged electrocardiogram; Also identified as an incidental finding in 1/30,716 individuals who underwent exome sequencing (Haggerty et al., 2017); although a follow-up cardiac evaluation was not reported; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 228620; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20031616, 23071725, 28471438, 31402444)
Fulgent Genetics, Fulgent Genetics RCV002500710 SCV002781617 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2021-10-07 criteria provided, single submitter clinical testing

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