ClinVar Genomic variation as it relates to human health

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).

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.

Has been reported previously in individuals with features of Charcot-Marie-Tooth (CMT) (PMID: 14638973, 19259128, 37747677); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26135405, 19259128, 15249646, 26310628, 20461396, 36567457, 37091313, 14638973, 37747677)

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.

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.