ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.1585C>T (p.Arg529Cys) (rs750529207)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484690 SCV000565563 likely pathogenic not provided 2013-12-30 criteria provided, single submitter clinical testing The Arg529Trp missense change in the SH3TC2 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. Two other amino acid substitutions at this same position (Arg529Cys and Arg529Gln) have been previously reported in association with CMT4C according to the Human Gene Mutation database. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged, non-polar Tryptophan residue at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, Arg529Trp is a strong candidate for a pathogenic variant, although the possibility that it is a benign variant cannot be excluded.
Invitae RCV000792222 SCV000931503 uncertain significance Charcot-Marie-Tooth disease type 4 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 529 of the SH3TC2 protein (p.Arg529Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs750529207, ExAC 0.01%). This variant has not been reported in the literature in individuals with SH3TC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 418488). 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. This variant disrupts the p.Arg529 amino acid residue in SH3TC2. Other variant(s) that disrupt this residue (p.Arg529Gln, p.Arg529Trp) have been observed in individuals with SH3TC2-related conditions (PMID: 14574644, 30001926), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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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