Submissions for variant NM_024577.4(SH3TC2):c.3379C>T (p.Arg1127Trp)

dbSNP: rs1580888993

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044556	SCV001208360	uncertain significance	Charcot-Marie-Tooth disease type 4	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 1127 of the SH3TC2 protein (p.Arg1127Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 23466821). ClinVar contains an entry for this variant (Variation ID: 637412). 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. 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.
Ambry Genetics	RCV002458407	SCV002614428	uncertain significance	Inborn genetic diseases	2021-06-03	criteria provided, single submitter	clinical testing	The p.R1127W variant (also known as c.3379C>T), located in coding exon 15 of the SH3TC2 gene, results from a C to T substitution at nucleotide position 3379. The arginine at codon 1127 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in the homozygous state in a Japanese patient with early-onset demyelinating Charcot-Marie-Tooth disease (CMT) (Hayashi M et al. J Hum Genet, 2013 May;58:273-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330952	SCV004037722	uncertain significance	not specified	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: SH3TC2 c.3379C>T (p.Arg1127Trp) results in a non-conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251480 control chromosomes (gnomAD). c.3379C>T has been reported in the literature in the homozygous state in an individual affected with Charcot-Marie Disease Type 4C (Hayashi_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Inherited Neuropathy Consortium	RCV000789573	SCV000928929	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only