Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000015238 | SCV000255799 | pathogenic | Charcot-Marie-Tooth disease, demyelinating, type 1b | 2013-11-06 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000237048 | SCV000292963 | pathogenic | not provided | 2018-09-07 | criteria provided, single submitter | clinical testing | The R98C pathogenic variant in the MPZ gene has been reported previously as a de novo finding in multiple unrelated individuals with MPZ-related disorders (Rouger et al., 1996; Baets et al., 2011). Functional studies suggest that R98C results in reduced transport of the MPZ protein to the plasma membrane (Lee et al., 2010; Saporta et al., 2012). The R98C variant is not observed in large population cohorts (Lek et al., 2016). The R98C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, multiple pathogenic missense variants at this residue (R98H/P) have been reported in association with MPZ-related disorders (Rouger et al., 1996; Stenson et al., 2014). Therefore, the presence of R98C is consistent with the diagnosis of a MPZ-related disorder in this individual. |
| Invitae | RCV000548074 | SCV000636242 | pathogenic | Charcot-Marie-Tooth disease, type I | 2018-09-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with cysteine at codon 98 of the MPZ protein (p.Arg98Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs121913590, ExAC no frequency). This variant has been reported in many individuals affected with Charcot-Marie-Tooth disease and Dejerine-Sottas syndrome (PMID: 9168174, 8644725, 20461396, 21840889, 8797476). In several of these individuals, it was shown to arise de novo (PMID: 9168174, 8644725, 8797476). ClinVar contains an entry for this variant (Variation ID: 14175). Experimental studies have shown that this missense change causes the retention of MPZ in the endoplasmic reticulum both in vitro and in vivo and recapitulates the Charcot-Marie-Tooth disease phenotype in mice (PMID: 22689911, 20461396). For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000015238 | SCV000035497 | pathogenic | Charcot-Marie-Tooth disease, demyelinating, type 1b | 1996-03-01 | no assertion criteria provided | literature only |