Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000519245 | SCV000617779 | likely pathogenic | not provided | 2017-09-18 | criteria provided, single submitter | clinical testing | A variant that is likely pathogenic has been identified in the MPZ gene. The D134N variant has been reported previously as a pathogenic variant in several family members with CMT1 (Nelis et al., 1994). The D134N variant is not observed in large population cohorts (Lek et al., 2016). The D134N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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 in nearby residues (I135T, G137S/A) have been reported in the Human Gene Mutation Database in association with MPZ-related disorders (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. |
| Athena Diagnostics Inc | RCV000519245 | SCV001880054 | likely pathogenic | not provided | 2020-11-18 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in one individual with clinical features associated with this gene. Computational tools predict that this variant is pathogenic. The variant is located in a region that is considered important for protein function and/or structure. |
| MGZ Medical Genetics Center | RCV002289708 | SCV002580892 | likely pathogenic | Charcot-Marie-Tooth disease type 1B | 2022-06-15 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002525120 | SCV003523470 | uncertain significance | Charcot-Marie-Tooth disease, type I | 2022-02-21 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Asp134 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10737979). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 449536). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 7527371). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 134 of the MPZ protein (p.Asp134Asn). |
| Inherited Neuropathy Consortium | RCV000789467 | SCV000928823 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |