Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000256065 | SCV000322234 | pathogenic | not provided | 2023-02-27 | criteria provided, single submitter | clinical testing | Reported in families with X-linked Charcot-Marie-Tooth disease in published literature (Bergoffen et at., 1993; Bone et al., 1995); Published functional studies demonstrate that L156R mutant formed defective junctional channels (Wang et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 15006706, 9361298, 7477983, 26955336, 8266101) |
| Labcorp Genetics |
RCV000463876 | SCV000544773 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2024-01-06 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 156 of the GJB1 protein (p.Leu156Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 7477983, 8266101, 9018031, 17353473, 26955336). ClinVar contains an entry for this variant (Variation ID: 10437). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 15006706). For these reasons, this variant has been classified as Pathogenic. |
| Athena Diagnostics | RCV000256065 | SCV000841717 | pathogenic | not provided | 2017-12-29 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002326674 | SCV002634487 | likely pathogenic | Inborn genetic diseases | 2020-06-12 | criteria provided, single submitter | clinical testing | The p.L156R variant (also known as c.467T>G), located in coding exon 1 of the GJB1 gene, results from a T to G substitution at nucleotide position 467. The leucine at codon 156 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). It has been identified in multiple individuals with X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) (Shy ME et al. Neurology, 2007 Mar;68:849-55; Siskind CE et al. J. Peripher. Nerv. Syst., 2011 Jun;16:102-7; Bergoffen J et al. Science, 1993 Dec;262:2039-42; Wu N et al. Case Rep Neurol Dec;7:247-52; Bone LJ et al. Neurology, 1995 Oct;45:1863-6). A functional study shows that this variant leads to reduced production of junctional current and has negative impacts on neurobiotin transfer (Wang HL et al. Neurobiol. Dis., 2004 Mar;15:361-70). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| OMIM | RCV000011182 | SCV000031409 | pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 1995-10-01 | no assertion criteria provided | literature only |