Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000201093 | SCV000255689 | pathogenic | Charcot-Marie-Tooth Neuropathy X Type 1 | 2014-11-19 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000234336 | SCV000283687 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2019-11-21 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glutamine at codon 15 of the GJB1 protein (p.Arg15Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many (>5) unrelated individuals affected with CMT (PMID: 8162049, 10586261, 11718056, 17353473, 18379723, 19062535, 22464564). In addition, this variant has been reported to segregate with disease in multiple families (PMID: 14706470, 15719046). ClinVar contains an entry for this variant (Variation ID: 217169). Experimental studies on the GJB1 encoded gap junction protein connexin 32 have shown that this missense change has no effect on protein localization or ability to form junctions (PMID: 9364054, 15006706), but does have a small effect on channel conductance (PMID: 11325342). Furthermore, a different missense substitution at this codon (p.Arg15Trp) is reported to be deleterious (PMID: 9328258, 10093067, 10639608, 11325342, 24078732). This indicates that the p.Arg15 residue is important for GJB1 protein function. In summary, this is a rare missense change that has been reported in affected individuals, segregates with disease, and affects a functionally important residue in the GJB1 protein. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000235929 | SCV000293139 | pathogenic | not provided | 2015-09-24 | criteria provided, single submitter | clinical testing | The R18Q variant has been previously reported in association with CMTX1 (Deschenes et al., 1997; Hahn et al., 1999; Fairweather et al., 1994). Functional studies show that R15Q alters the conductance voltage of the channel (Abrams et al. 2001). 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. R15Q is a semi-conservative amino acid substitution, which occurs at a position where amino acids with similar properties to Arginine are tolerated across species. A different amino acid substitution at this same position (R15W) and many missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, R15Q is interpreted to be a pathogenic variant, and its presence is consistent with a diagnosis of CMTX1 |