Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000235814 | SCV000293448 | likely pathogenic | not provided | 2021-08-20 | criteria provided, single submitter | clinical testing | Functional studies show that the Q80R variant is capable of forming a functional gap junction protein, and the authors conclude that further functional studies are necessary to elucidate the effect, if any, of the Q80R variant (Wang et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30042657, 25449862, 15006706, 9361298, 28211240, 17353473, 8737658, 10873293, 10737979, 7580242) |
| Invitae | RCV000466555 | SCV000544779 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 80 of the GJB1 protein (p.Gln80Arg). 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: 7580242, 10737979, 17353473; Invitae). ClinVar contains an entry for this variant (Variation ID: 246096). 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 does not substantially affect GJB1 function (PMID: 15006706). This variant disrupts the p.Gln80 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 22464564, 28286897), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Athena Diagnostics Inc | RCV000235814 | SCV000613480 | pathogenic | not provided | 2016-12-22 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002450732 | SCV002738503 | uncertain significance | Inborn genetic diseases | 2022-08-22 | criteria provided, single submitter | clinical testing | The p.Q80R variant (also known as c.239A>G), located in coding exon 1 of the GJB1 gene, results from an A to G substitution at nucleotide position 239. The glutamine at codon 80 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in individuals with features consistent with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1); however, clinical details were limited (Mersiyanova IV et al. Hum Mutat, 2000;15:340-7; Ionasescu V et al. Am J Med Genet, 1996 Jun;63:486-91). Functional studies in vitro have shown that Q80R retains its ability to form homotypic junctional channels, similar to wild-type cells (Wang HL et al. Neurobiol Dis, 2004 Mar;15:361-70). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Inherited Neuropathy Consortium | RCV000789226 | SCV000928578 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |