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 | 2020-06-15 | criteria provided, single submitter | clinical testing | This sequence change replaces valine with glycine at codon 189 of the GJB1 protein (p.Val189Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with X-linked Charcot-Marie-Tooth disease (PMID: 9361298, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 420023). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. |
| Inherited Neuropathy Consortium | RCV000789819 | SCV000929203 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |