ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.1298C>T (p.Ser433Leu) (rs200967041)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723677 SCV000331420 uncertain significance not provided 2017-07-10 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000404986 SCV000615235 uncertain significance not specified 2017-06-07 criteria provided, single submitter clinical testing
GeneDx RCV000723677 SCV000618252 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SH3TC2 gene. The S433L variant has been previously reported in a compound heterozygous state in an individual undergoing testing for hereditary neuropathy, who, upon further examination did not have evidence of neuropathy; therefore, the authors concluded that the pathogenicity of the S433L variant remains uncertain (Laššuthová et al., 2011). The S433Lvariant is observed in 10/6614 (0.2%) alleles from individuals of European background, and in the homozygous state in an unaffected individual referred for testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S433L 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. This substitution occurs at a position that is conserved in mammals, an in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the 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 RCV000558978 SCV000657892 uncertain significance Charcot-Marie-Tooth disease type 4 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 433 of the SH3TC2 protein (p.Ser433Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs200967041, ExAC 0.2%). This variant has been reported in 2 individuals affected with Charcot-Marie-Tooth disease (PMID: 21291453, 25025039). ClinVar contains an entry for this variant (Variation ID: 281116). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, this variant has uncertain impact on SH3TC2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Inherited Neuropathy Consortium RCV000789696 SCV000929072 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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