ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.1928C>T (p.Thr643Met) (rs150643310)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756899 SCV000884871 uncertain significance not provided 2017-07-07 criteria provided, single submitter clinical testing The p.Thr643Met variant (rs150643310) has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.004% (identified in 12 out of 277,074 chromosomes). The threonine at codon 643 is highly conserved considering 13 species up to C. elegans (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on VCL protein structure/function (SIFT: damaging, PolyPhen2: damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Thr643Met variant cannot be determined with certainty.
Invitae RCV000818461 SCV000959076 uncertain significance Dilated cardiomyopathy 1W 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 643 of the VCL protein (p.Thr643Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs150643310, ExAC 0.008%). This variant has not been reported in the literature in individuals with VCL-related disease. ClinVar contains an entry for this variant (Variation ID: 487627). 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 and their clinical significance is uncertain. 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.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656206 SCV000678400 uncertain significance Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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