Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000480241 | SCV000568358 | likely pathogenic | not provided | 2017-03-14 | criteria provided, single submitter | clinical testing | A variant that is likely pathogenic has been identified in the GJB1 gene. The V189G variant has been previously reported as a pathogenic variant in an individual with CMTX1; however, no further information was provided (Bone et al., 1997). A different amino acid substitution a the same position (V189I) has also been reported in an individual with CMTX1; however, no further information was provided (Bone et al., 1997). The V189G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position in the extracellular topological domain where amino acids with similar properties to Valine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the V189G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. |
| Invitae | RCV000809132 | SCV000949273 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2023-08-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 420023). This missense change has been observed in individuals with X-linked Charcot-Marie-Tooth disease (PMID: 9361298; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 189 of the GJB1 protein (p.Val189Gly). |
| Inherited Neuropathy Consortium | RCV000789819 | SCV000929203 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |