ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.3127G>T (p.Ala1043Ser) (rs200819602)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520904 SCV000620007 uncertain significance not provided 2018-11-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SH3TC2 gene. The A1043S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A1043S variant is observed in 21/126512 (0.02%) alleles from individuals of non-Finnish European background (Lek et al., 2016). The A1043S 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. However, in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000536439 SCV000657922 uncertain significance Charcot-Marie-Tooth disease type 4 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 1043 of the SH3TC2 protein (p.Ala1043Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs200819602, ExAC 0.01%) but has not been reported in the literature in individuals with an SH3TC2-related disease. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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