Submissions for variant NM_000530.8(MPZ):c.418T>A (p.Ser140Thr)

gnomAD frequency: 0.00001  dbSNP: rs572010627

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000518262	SCV000614110	likely pathogenic	not provided	2016-08-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703449	SCV000832348	pathogenic	Charcot-Marie-Tooth disease, type I	2025-01-14	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. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MPZ variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 11,906 individuals referred to our laboratory for MPZ testing. This variant is also known as c.752T>A or p.Ser111Thr. ClinVar contains an entry for this variant (Variation ID: 447730). Invitae Evidence 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 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, Molecular Genetics and Genomics, 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, London Health Sciences Centre	RCV000789485	SCV001336814	likely pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000518262	SCV005199167	likely pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000789485	SCV000928841	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only