Submissions for variant NM_024422.6(DSC2):c.1679C>T (p.Thr560Met)

gnomAD frequency: 0.00001  dbSNP: rs772775522

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001365691	SCV001561968	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-07-05	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 560 of the DSC2 protein (p.Thr560Met). This variant is present in population databases (rs772775522, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1056810). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV001751723	SCV001995005	uncertain significance	not provided	2019-08-28	criteria provided, single submitter	clinical testing	Has not been previously published in individuals with DSC2-related disease to our knowledge; 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: 30942563)
Color Diagnostics, LLC DBA Color Health	RCV001806149	SCV002052907	uncertain significance	Cardiomyopathy	2023-08-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 560 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/250114 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.
All of Us Research Program, National Institutes of Health	RCV004006791	SCV004816137	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 560 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/250114 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.