ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.391G>A (p.Ala131Thr) (rs373542380)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000037304 SCV000233481 uncertain significance not specified 2016-02-17 criteria provided, single submitter clinical testing The A131T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A131T variant was not observed with any significant frequency in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A131T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000525744 SCV000641986 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-08-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 131 of the DSG2 protein (p.Ala131Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs373542380, ExAC 0.009%) but has not been reported in the literature in individuals with a DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 44316). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627165 SCV000748028 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2017-07-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770545 SCV000901992 uncertain significance Cardiomyopathy 2015-10-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037304 SCV000060961 uncertain significance not specified 2014-11-11 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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