Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000518262 | SCV000614110 | likely pathogenic | not provided | 2016-08-16 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000703449 | SCV000832348 | pathogenic | Charcot-Marie-Tooth disease, type I | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 140 of the MPZ protein (p.Ser140Thr). This variant is present in population databases (rs572010627, gnomAD 0.002%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 12207932, 14711881, 26310628). It has also been observed to segregate with disease in related individuals. This variant is also known as c.752T>A or p.Ser111Thr. ClinVar contains an entry for this variant (Variation ID: 447730). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MPZ protein function. This variant disrupts the p.Ser140 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12207932, 22433810, 24028194). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV001002532 | SCV001160495 | likely pathogenic | not specified | 2019-05-02 | criteria provided, single submitter | clinical testing | The MPZ c.418T>A; p.Ser140Thr variant (rs572010627), also known as p.Ser111Thr using alternative nomenclature, is reported in the literature in multiple individuals affected with Charcot-Marie-Tooth (CMT) disease (Sanmaneechai 2015, Shy 2004, Son 2017, Street 2002). In one family, this variant was observed to co-segregate with disease in four affected individuals and was absent from two unaffected relatives (Street 2002). This variant is found on only two chromosomes in the Genome Aggregation Database (2/251496 alleles), indicating it is not a common polymorphism, and it is reported as pathogenic/likely pathogenic by several laboratories in ClinVar (Variation ID: 447730). The serine at codon 140 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, this variant occurs in the MPZ extracellular domain within a cluster of amino acids frequently substituted in individuals with CMT (p.Thr139Asn, p.Lys138Asn, p.Gly137Ser) (Shy 2004). Based on available information, the p.Ser140Thr variant is considered to be likely pathogenic. References: Sanmaneechai O et al. Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene. Brain. 2015 Nov;138(Pt 11):3180-92. Shy ME et al. Phenotypic clustering in MPZ mutations. Brain. 2004 Feb;127(Pt 2):371-84. Son D et al. Generation of induced pluripotent stem cell (iPSC) line from Charcot-Marie-Tooth disease patient with MPZ mutation (CMT1B). Stem Cell Res. 2017 Oct;24:5-7. Street VA et al. Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes. Neuromuscul Disord. 2002 Oct;12(7-8):643-50. |
| Molecular Genetics Laboratory, |
RCV000789485 | SCV001336814 | likely pathogenic | Charcot-Marie-Tooth disease | criteria provided, single submitter | clinical testing | ||
| Inherited Neuropathy Consortium | RCV000789485 | SCV000928841 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |