ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.3512G>T (p.Arg1171Leu) (rs200728983)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236255 SCV000292859 pathogenic not provided 2015-05-14 criteria provided, single submitter clinical testing The R1171L variant has been previously reported as a homozygous pathogenic variant in a young adult with motor and sensory neuropathy, reduced nerve conduction velocity, and a family history suggestive of an autosomal recessive disorder (Yger et al., 2012). Additionally, a different amino acid substitution at the same position (R1171C) has been published as a homozygous mutation in a patient with CMT4C (Hayashi et al., 2013). R1171L was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R1171L is a non-conservative amino acid substitution that alters a position in the protein that is conserved across species. In silico analysis predicts this variant is probably damaging to protein structure/function. Therefore, R1171L is interpreted to be a disease-causing variant
Invitae RCV001064903 SCV001229838 uncertain significance Charcot-Marie-Tooth disease type 4 2019-05-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 1171 of the SH3TC2 protein (p.Arg1171Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs200728983, ExAC 0.02%). This variant has been observed to be homozygous in an individual affected with Charcot-Marie-Tooth disease type 4C (PMID: 22462672). ClinVar contains an entry for this variant (Variation ID: 245766). 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. This variant disrupts the p.Arg1171 amino acid residue in SH3TC2. Other variant(s) that disrupt this residue have been observed in individuals with SH3TC2-related conditions (PMID: 23466821), which suggests that this may be a clinically significant amino acid residue. 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.
Molecular Genetics Laboratory,London Health Sciences Centre RCV000790211 SCV001335900 likely pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000790211 SCV000929603 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Genesis Genome Database RCV000790211 SCV000999714 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research

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