Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
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. |
| Labcorp Genetics |
RCV000460808 | SCV000544767 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 26 of the GJB1 protein (p.Ser26Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type 1X (PMID: 8990008, 9354338, 11271367, 21291455, 25429913, 25802885, 27862672). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 155726). 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. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9354338, 16442804, 27844031). For these reasons, this variant has been classified as Pathogenic. |
| Athena Diagnostics | 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. |
| ARUP Laboratories, |
RCV000143795 | SCV002049616 | pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 2021-01-12 | criteria provided, single submitter | clinical testing | The GJB1 c.77C>T; p.Ser26Leu variant (rs587777876) is reported in the literature in multiple individuals affected with X-linked Charcot-Marie-Tooth disease (selected references: Yoshimura 1996, Hsu 2019, and Niu 2020). In vitro functional analyses demonstrate that the p.Ser26Leu alters the channels junctional permeability by reducing the pore size (Tsai 2016). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. |
| Northcott Neuroscience Laboratory, |
RCV000143795 | SCV000188687 | pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | no assertion criteria provided | not provided | Converted during submission to Pathogenic. |