ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.292C>T (p.Arg98Cys) (rs121913590)

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Total submissions: 4
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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
GeneDx 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

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