ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.901A>G (p.Thr301Ala) (rs576466497)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181145 SCV000233422 uncertain significance not provided 2016-12-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSC2 gene. The T301A variant has not been publishedas a pathogenic variant, nor has it been reported as a benign variant to our knowledge. T301A was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was notobserved with any significant frequency in the Exome Aggregation Consortium (ExAC). Although this substitutionoccurs at a position that is conserved, A301 is present in at least one species. Nevertheless, the T301A variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differin polarity, charge, size and/or other properties. Furthermore, in silico analysis predicts this variant is probablydamaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000818516 SCV000959134 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 301 of the DSC2 protein (p.Thr301Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs576466497, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 199764). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; 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.

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