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 | 2018-06-17 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with cysteine at codon 111 of the MPZ protein (p.Ser111Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 19293842, 26310628, 25429913). ClinVar contains an entry for this variant (Variation ID: 449538). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Ser111Phe, also referred to as p.Ser121Phe) has been reported in an individual affected with Charcot-Marie-Tooth disease (PMID: 22176150). 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. |
| Inherited Neuropathy Consortium | RCV000790095 | SCV000929485 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |