ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.1325C>T (p.Pro442Leu) (rs370613184)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523748 SCV000621474 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing The P442L variant in the SH3TC2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P442L variant is observed in 5/30776 (0.016%) alleles from individuals of South Asian background, in large population cohorts (Lek et al., 2016). The P442L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P442L as a variant of uncertain significance.
Invitae RCV000654135 SCV000776025 uncertain significance Charcot-Marie-Tooth disease type 4 2018-01-10 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 442 of the SH3TC2 protein (p.Pro442Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs370613184, ExAC 0.02%). This variant has not been reported in the literature in individuals with SH3TC2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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