ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.181C>T (p.Arg61Cys) (rs773087313)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001041503 SCV001205124 uncertain significance Charcot-Marie-Tooth disease type 4 2019-03-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 61 of the SH3TC2 protein (p.Arg61Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs773087313, ExAC 0.01%). This variant has not been reported in the literature in individuals with SH3TC2-related conditions. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001257248 SCV001433785 uncertain significance not provided 2017-06-07 criteria provided, single submitter clinical testing The p.Arg61Cys variant (rs773087313) 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 0.002% (identified in 5 out of 277,194 chromosomes). The arginine at codon 61 is highly conserved considering 8 species up to Zebrafish (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on SH3TC2 protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Arg61Cys variant cannot be determined with certainty.

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