ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.2812C>T (p.His938Tyr) (rs144688852)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518778 SCV000615244 uncertain significance not specified 2017-06-13 criteria provided, single submitter clinical testing
GeneDx RCV000657143 SCV000618160 uncertain significance not provided 2018-01-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SH3TC2 gene. The H938Y variant has been reported previously with a R964X pathogenic variant in an individual with inherited peripheral neuropathy (Laššuthová et al., 2016). The H938Y variant is observed in 85/126638 (0.067%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The H938Y 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 analyses, including protein predictors and evolutionary conservation, support 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 RCV000654132 SCV000776022 uncertain significance Charcot-Marie-Tooth disease type 4 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 938 of the SH3TC2 protein (p.His938Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs144688852, ExAC 0.05%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with an inherited peripheral neuropathy (IPN) (PMID: 27549087). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 448368). 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 tolerated, 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.

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