ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.289G>A (p.Ala97Thr) (rs562689036)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000809649 SCV000949813 uncertain significance Charcot-Marie-Tooth disease type 4 2018-07-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 97 of the SH3TC2 protein (p.Ala97Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs562689036, ExAC 0.1%). 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 (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.
Diagnostics Lab (ASPIRE), CSIR - Centre for Cellular and Molecular Biology RCV001030798 SCV001190225 uncertain significance Hereditary motor and sensory neuropathy 2019-12-24 criteria provided, single submitter clinical testing The c.289G>A variant is not present in publicly available database like Exome Variant Server (EVS), however present in 1000 Genomes, Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP at a low minor allele frequency (MAF<0.001), in heterozygous state. The variant is present in our in-house exome database in heterozygous state (MAF~0.00259). This variant was not reported earlier in OMIM, ClinVar and HGMD databases in any other affected individuals. In-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD etc. predicted this variant as likely deleterious, however functional assay was not done to prove this. Due to lack of enough evidence the variant has been classified as uncertain significance. The variant was observed in compound heterozygous state with an another missense variant (c.1942C>T) in SH3TC2 gene (ClinVar Accession ID: VCV000351908.2)

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