ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.418T>A (p.Ser140Thr) (rs572010627)

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Total submissions: 5
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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 2018-02-23 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 140 of the MPZ protein (p.Ser140Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs572010627, ExAC 0.003%). This variant has been reported to segregate with Charcot-Marie-Tooth disease in a family (PMID: 12207932) and has been reported in individuals affected with Charcot-Marie-Tooth disease (PMID: 26310628, 14711881). This variant is also known as c.752T>A or p.Ser111Thr in the literature. ClinVar contains an entry for this variant (Variation ID: 447730). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Ser140Cys) has been determined to be likely pathogenic (PMID: 24028194, 22433810, 12207932 ). This suggests that the serine residue is critical for MPZ protein function and that other missense substitutions at this position may also be pathogenic. 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
Inherited Neuropathy Consortium RCV000789485 SCV000928841 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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