ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.880C>A (p.Leu294Ile)

gnomAD frequency: 0.00001  dbSNP: rs761796202
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000690201 SCV000817880 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2022-02-03 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 569544). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is present in population databases (rs761796202, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 294 of the DSC2 protein (p.Leu294Ile).
GeneDx RCV001756175 SCV001987321 uncertain significance not provided 2019-05-10 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 569544; 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 that this variant does not alter protein structure/function
Color Diagnostics, LLC DBA Color Health RCV003532232 SCV004363109 uncertain significance Cardiomyopathy 2023-07-20 criteria provided, single submitter clinical testing This missense variant replaces leucine with isoleucine at codon 294 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 been identified in 1/251428 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.

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