Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000205076 | SCV000259731 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2022-02-18 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects GJB1 function (PMID: 27844031). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 219704). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (CMT) (PMID: 27844031; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 215 of the GJB1 protein (p.Arg215Pro). This variant disrupts the p.Arg215 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8162049, 8816997). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000236627 | SCV000293721 | likely pathogenic | not provided | 2016-01-15 | criteria provided, single submitter | clinical testing | The R215P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R215P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a different amino acid substitution at the same position (R215W) and several missense variants in nearby residues have been reported in the Inherited Peripheral Neuropathy (IPN) database and Human Gene Mutation Database in association with CMTX1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Institute of Medical Genetics and Applied Genomics, |
RCV002466254 | SCV002761193 | likely pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 2022-12-13 | criteria provided, single submitter | clinical testing |