ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.3380G>A (p.Arg1127Gln) (rs139192433)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214292 SCV000279172 uncertain significance not provided 2017-06-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SH3TC2 gene. This variant was observed in the heterozygous state in 3 individuals with symptoms of CMT1 and was described as being a variant of unknown significance (Antoniadi et al., 2015). A missense variant in the same residue (R1127W) has been reported in the Human Gene Mutation Database in association with SH3TC2-related disease (Stenson et al., 2014). The 1000 Genomes Project reports R1127Q was observed in 2/182 (1.1%) alleles from individuals of British background, and the NHLBI Exome Sequencing Project reports R1127Q was observed in 19/8600 (0.2%) alleles from individuals of European background. The R1127Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably 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.
Illumina Clinical Services Laboratory,Illumina RCV000473910 SCV000454522 uncertain significance Charcot-Marie-Tooth disease type 4 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000355518 SCV000454523 uncertain significance Mononeuropathy of the Median Nerve 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000473910 SCV000546363 uncertain significance Charcot-Marie-Tooth disease type 4 2018-06-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1127 of the SH3TC2 protein (p.Arg1127Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs139192433, ExAC 0.2%). This variant has been reported in the heterozygous state in three individuals affected with Charcot-Marie-Tooth disease. However, a second variant in the SH3TC2 gene was not reported on the opposite allele in these individuals (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 234414). 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.

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