Submissions for variant NM_000166.6(GJB1):c.77C>T (p.Ser26Leu) (rs587777876)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437610	SCV000520913	pathogenic	not provided	2018-06-26	criteria provided, single submitter	clinical testing	The S26L missense variant in the GJB1 gene has been reported previously in association with CMTX1 (Oh et al., 1997; Nelis et al., 1997; Sun et al., 2016). Functional analysis shows that S26L alters the structure and permeability of the membrane (Oh et al., 1997). The S26L variant is not observed in large population cohorts (Lek et al., 2016). The S26L 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. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with CMTX1 (Stenson et al., 2014). Therefore, S26L is interpreted to be a pathogenic variant.
Invitae	RCV000460808	SCV000544767	pathogenic	Charcot-Marie-Tooth Neuropathy X	2019-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine with leucine at codon 26 of the GJB1 protein (p.Ser26Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (rs587777876, ExAC no frequency). This variant has been reported in many individuals affected with Charcot-Marie-Tooth disease, type 1X (PMID: 8990008, 25429913, 27862672, 11271367, 21291455). It has also been reported to segregate with disease in affected families (PMID: 9354338, 25802885). ClinVar contains an entry for this variant (Variation ID: 155726) Experimental studies have shown that this variant reduces the pore size of the connexin-32 protein channel which reduces its permeability and impairs proper function (PMID: 9354338, 16442804, 27844031). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000437610	SCV001143685	pathogenic	not provided	2019-01-29	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/204891 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease in affected and unaffected individuals, but from a single family. One de novo case without parental identity confirmed.
Northcott Neuroscience Laboratory, ANZAC Research Institute	RCV000143795	SCV000188687	pathogenic	Charcot-Marie-Tooth Neuropathy X Type 1		no assertion criteria provided	not provided	Converted during submission to Pathogenic.