Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000523011 | SCV000617781 | likely pathogenic | not provided | 2017-08-10 | criteria provided, single submitter | clinical testing | A variant that is likely pathogenic has been identified in the MPZ gene. The S111C variant has been previously reported in several individuals with a clinical diagnosis of CMT (Mandich et al., 2009, Manganelli et al., 2014, Sanmaneechai et al., 2015). The S111C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S111C 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 that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants at the same (S111P) and in nearby residues (D109N/E, G110D, I112T) have been reported in Human Gene Mutation Database in association with MPZ-related neuropathies (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. |
| Invitae | RCV000704378 | SCV000833325 | likely pathogenic | Charcot-Marie-Tooth disease, type I | 2022-08-09 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser111 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22176150). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MPZ function (PMID: 29687021). 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. ClinVar contains an entry for this variant (Variation ID: 449538). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 19293842; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 111 of the MPZ protein (p.Ser111Cys). |
| Inherited Neuropathy Consortium | RCV000790095 | SCV000929485 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |