Submissions for variant NM_024577.3(SH3TC2):c.1972C>T (p.Arg658Cys) (rs80338926)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236498	SCV000292951	likely pathogenic	not provided	2018-02-23	criteria provided, single submitter	clinical testing	The R658C missense variant in the SH3TC2 gene has been reported previously in multiple families with CMT, at least two of whom who were also heterozygous for the R954X pathogenic variant (Senderek et al.,2003; Azzedine et al., 2006; Lassuthova et al., 2011). Functional studies show that R658C alters protein localization (Lupo et al., 2009; Roberts et al., 2010). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R658C 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 where amino acids with similar properties to Arginine are tolerated across species. Based on currently available evidence, R658C is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded.
GeneReviews	RCV000020888	SCV000041484	pathologic	Charcot-Marie-Tooth disease, type 4C	2008-03-31	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Invitae	RCV000654080	SCV000775970	likely pathogenic	Charcot-Marie-Tooth disease type 4	2017-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 658 of the SH3TC2 protein (p.Arg658Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80338926, ExAC 0.01%). This variant has been found to segregate with Charcot-Marie-Tooth disease type 4C in affected families (PMID: 14574644, 21291453). It has also been reported in the homozygous state in an affected individual (PMID: 16924012). ClinVar contains an entry for this variant (Variation ID: 21690). Experimental studies have shown that this missense change impacts SH3TC2 cellular localization in vitro (PMID: 19744956). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.