Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000521368 | SCV000617783 | uncertain significance | not specified | 2017-07-21 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the MPZ gene. The I89N variant has been previously reported in a patient with CMT2 who also had two other MPZ variants, I162M and V92M; analysis of cloned PCR fragments was consistent with all 3 alleles being present on the same allele (in cis) (Boerkoel et al., 2001). The I89N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I89N 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. Missense variants in nearby residues (Y88H, D90H/E, V92M, G93E) have been reported in the Human Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, the majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014). However, this substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV001339130 | SCV001532851 | uncertain significance | Charcot-Marie-Tooth disease, type I | 2023-02-27 | 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 sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 89 of the MPZ protein (p.Ile89Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 11835375). ClinVar contains an entry for this variant (Variation ID: 242786). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MPZ protein function. |