Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000545060 | SCV000658910 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 139 of the GJB1 protein (p.Val139Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 7477983, 8266101, 9272161, 9364054). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10433). 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 not expected to disrupt GJB1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 8816997, 11325342). For these reasons, this variant has been classified as Pathogenic. |
| Laboratório de Neurologia Aplicada e Experimental, |
RCV000011178 | SCV001934604 | pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 2021-07-20 | criteria provided, single submitter | research | 3. The p.Val139Met variant in GJB1 has been reported in several families worldwide with Charcot-Marie-Tooth Neuropathy X linked. ClinVar classifies this variant as Pathogenic (Variation ID:10433), 1 star (criteria provided, 4 submissions), citing 7 articles (12402337, 11325342, 9364054, 9272161, 8816997 and 2 more). This variant is in a hotspot region and an important functional domain of the protein (M3). Besides that, this variant segregates with family phenotype. In summary, the p.Val139Met meets our criteria to be classified as pathogenic. |
| Mendelics | RCV000011178 | SCV002516469 | pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV002274895 | SCV002564117 | pathogenic | not provided | 2022-07-01 | criteria provided, single submitter | clinical testing | GJB1: PP1:Strong, PM2, PM5, PS4:Moderate |
| Ambry Genetics | RCV002326673 | SCV002628080 | pathogenic | Inborn genetic diseases | 2021-01-15 | criteria provided, single submitter | clinical testing | The p.V139M pathogenic mutation (also known as c.415G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 415. The valine at codon 139 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1), and it has been found to segregate with CMTX1 in multiple families (Bergoffen J et al. Science, 1993 Dec;262:2039-42; Fain PR et al. Am J Hum Genet, 1994 Feb;54:229-35; Halbrich M et al. Can J Neurol Sci, 2008 Jul;35:372-4; Hoebeke C et al. Arch Pediatr, 2018 Nov;25:452-458; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Silander K et al. Hum Genet, 1997 Sep;100:391-7). Functional studies indicate that this alteration impairs gap junction formation and results in altered pattern of trafficking and localization (Omori Y et al. Mol Biol Cell, 1996 Jun;7:907-16; Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; Abrams CK et al. Brain Res, 2001 May;900:9-25; Abrams CK et al. Sci Rep, 2017 01;7:40166). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Fulgent Genetics, |
RCV000011178 | SCV002785190 | pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 2021-09-11 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV002274895 | SCV004226240 | pathogenic | not provided | 2023-03-14 | criteria provided, single submitter | clinical testing | PP1_strong, PM5, PS3, PS4 |
| OMIM | RCV000011178 | SCV000031405 | pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 1995-10-01 | no assertion criteria provided | literature only | |
| Gene |
RCV000011178 | SCV000040504 | not provided | Charcot-Marie-Tooth disease X-linked dominant 1 | no assertion provided | literature only | ||
| Inherited Neuropathy Consortium | RCV000789810 | SCV000929194 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |