ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.746C>A (p.Thr249Asn)

gnomAD frequency: 0.00001  dbSNP: rs1987447409
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001233448 SCV001406043 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2022-07-30 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 960002). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 249 of the DSC2 protein (p.Thr249Asn).
GeneDx RCV001549925 SCV001770165 uncertain significance not provided 2020-11-18 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Ambry Genetics RCV002393581 SCV002671340 uncertain significance Cardiovascular phenotype 2022-03-19 criteria provided, single submitter clinical testing The p.T249N variant (also known as c.746C>A), located in coding exon 6 of the DSC2 gene, results from a C to A substitution at nucleotide position 746. The threonine at codon 249 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV004004851 SCV004841153 uncertain significance Familial isolated arrhythmogenic right ventricular dysplasia 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces threonine with asparagine at codon 249 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 DSC2-related disorders in the literature. This variant has not been identified 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.

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