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

Total submissions: 4

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.