Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000799870 | SCV000939552 | uncertain significance | Charcot-Marie-Tooth disease, type I | 2023-08-17 | 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.Ile62 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10214757, 11935267). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 14194). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 14638973). This variant is present in population databases (rs121913605, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 62 of the MPZ protein (p.Ile62Met). |
| Centre for Mendelian Genomics, |
RCV001196641 | SCV001367261 | uncertain significance | Roussy-Lévy syndrome | 2019-08-27 | criteria provided, single submitter | clinical testing | This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM5,PP5. |
| MGZ Medical Genetics Center | RCV000015258 | SCV002581392 | likely pathogenic | Charcot-Marie-Tooth disease type 2I | 2022-03-14 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV003736538 | SCV004562503 | uncertain significance | not provided | 2023-09-01 | criteria provided, single submitter | clinical testing | The MPZ c.186C>G; p.Ile62Met variant is reported in the literature in one individual affected with late onset Charcot-Marie-Tooth 2 syndrome (Auer-Grumbach 2003). This variant is also reported in ClinVar (Variation ID: 14194) and is found in the non-Finnish European population with an overall allele frequency of 0.0012% (3/251308 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (c.184A>T, p.Ile62Phe) has been reported in four related individuals with autosomal dominant motor and sensory neuropathy with focally folded myelin sheaths (Nakagawa 1999) and in vitro functional analysis of the p.Ile62Phe variant demonstrated dysregulation of adhesion function of the MPZ protein associated with abnormal myelin folding (Matsuyama 2002). Computational analyses of the p.Ile62Met, however, are uncertain whether this variant is neutral or deleterious (REVEL: 0.276). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Auer-Grumbach M et al. Late onset Charcot-Marie-Tooth 2 syndrome caused by two novel mutations in the MPZ gene. Neurology. 2003 Nov 25;61(10):1435-7. PMID: 14638973. Nakagawa M et al. A novel MPZ gene mutation in dominantly inherited neuropathy with focally folded myelin sheaths. Neurology. 1999 Apr 12;52(6):1271-5. PMID: 10214757. Matsuyama W et al. Altered trafficking and adhesion function of MPZ mutations and phenotypes of Charcot-Marie-Tooth disease 1B. Acta Neuropathol. 2002 May;103(5):501-8. PMID: 11935267. |
| OMIM | RCV000015258 | SCV000035517 | pathogenic | Charcot-Marie-Tooth disease type 2I | 2003-11-25 | no assertion criteria provided | literature only | |
| Practice for Gait Abnormalities, |
RCV003318543 | SCV004023202 | likely pathogenic | Tip-toe gait | 2022-11-15 | no assertion criteria provided | clinical testing |