Submissions for variant NM_000166.6(GJB1):c.132G>C (p.Trp44Cys) (rs879253935)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235491	SCV000292852	likely pathogenic	not provided	2015-05-18	criteria provided, single submitter	clinical testing	The W44C variant has been reported previously in association with CMTX1 (Stenson et al., 2014). Additionally, a different amino acid substitution at the same position (W44L) and many nearby missense variant (A40T/V, E41K/D, S42C, V43M, D46G, E47G, S49P/Y) have been published in association with CMT (Stenson et al., 2014). W44C 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. The W44C 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 that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae	RCV001068519	SCV001233635	likely pathogenic	Charcot-Marie-Tooth Neuropathy X	2019-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan with cysteine at codon 44 of the GJB1 protein (p.Trp44Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hereditary motor sensory neuropathy (PMID: 23011429). ClinVar contains an entry for this variant (Variation ID: 245761). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB1 protein function. This variant disrupts the p.Trp44 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 23011429), which suggests that this may be a clinically significant amino acid residue. 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.
Inherited Neuropathy Consortium	RCV000789296	SCV000928649	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only