VCV000447730.22 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (3); Likely pathogenic (5)

8 out of 9 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 447730 Accession: VCV000447730.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q23.3 1: 161306738 (GRCh38) [ NCBI UCSC ] 1: 161276528 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 19, 2017	Sep 22, 2026	Oct 23, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000530.8:c.418T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000521.2:p.Ser140Thr	missense
NM_001315491.2:c.418T>A	NP_001302420.1:p.Ser140Thr	missense
NC_000001.11:g.161306738A>T
NC_000001.10:g.161276528A>T
NG_008055.1:g.8235T>A
LRG_256:g.8235T>A
LRG_256t1:c.418T>A

... more HGVS ... less HGVS

Protein change

S140T

Other names

Canonical SPDI

NC_000001.11:161306737:A:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA1210178 dbSNP: rs572010627 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MPZ		Some evidence for dosage pathogenicity	Little evidence for dosage pathogenicity	GRCh38 GRCh37	729	766

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 13, 2022	RCV000518262.3
Charcot-Marie-Tooth disease, type I	Pathogenic (1)	criteria provided, single submitter	Apr 27, 2025	RCV000703449.9
Charcot-Marie-Tooth disease	Likely pathogenic (2)	criteria provided, single submitter	-	RCV000789485.2
not specified	Likely pathogenic (1)	criteria provided, single submitter	May 2, 2019	RCV001002532.8
Charcot-Marie-Tooth disease type 1B	Likely pathogenic (1)	criteria provided, single submitter	Sep 23, 2025	RCV006635477.1
MPZ-related polyneuropathy	Pathogenic (1)	criteria provided, single submitter	Oct 23, 2025	RCV006646127.2
MPZ-related disorder	Pathogenic (1)	criteria provided, single submitter	Jan 23, 2023	RCV006842121.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Aug 16, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics Criteria)	not provided	Athena Diagnostics Accession: SCV000614110.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (3) PubMed: 12207932‚ 14711881‚ 26310628 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (May 02, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	not specified	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001160495.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Charcot-Marie-Tooth disease	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001336814.1 First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Apr 27, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Charcot-Marie-Tooth disease, type I	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000832348.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026	Publications: PubMed (6) PubMed: 12207932‚ 14711881‚ 22433810‚ 24028194‚ 26310628‚ 28492532 Comment: show 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 13,236 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely Pathogenic (Sep 23, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Variantyx Assertion Criteria 2022)	Charcot-Marie-Tooth disease type 1B (Autosomal dominant inheritance)	Variantyx, Inc. Accession: SCV007520029.1 First in ClinVar: Mar 28, 2026 Last updated: Mar 28, 2026	Publications: PubMed (2) PubMed: 12207932‚ 36203352 Comment: show This is a nonsynonymous variant in the MPZ gene (OMIM: 159440). Pathogenic variants in this gene have been associated with autosomal dominant Charcot-Marie-Tooth disease type 1B (CMT1B). This variant has been reported in at least 2 unrelated affected individuals (PMID: 12207932, 36203352) (PS4_Moderate) and observed to segregate with disease in at least 3 individuals from one family (PMID: 12207932 ) (PP1). This variant lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the MPZ protein (PM1) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.692) (PP3). This variant has a 0.0009% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as likely pathogenic for autosomal dominant Charcot-Marie-Tooth disease type 1B (CMT1B). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Jul 13, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199167.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Oct 23, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	MPZ-related polyneuropathy	Clinical Genetics Laboratory, Region Ostergotland Accession: SCV007539068.2 First in ClinVar: Apr 12, 2026 Last updated: Jun 14, 2026	Publications: PubMed (4) PubMed: 12207932‚ 14711881‚ 26310628‚ 37273706 Comment: show The NM_000530.8:c.418T>A missense variant (REVEL score = 0.692) is rare in population database (0.00047% gnomAD-nonUKB v4.1.0) and is located in a cluster of amino acids in the MPZ ex- tracellular domain where substitutions are reported as disease causing (PMID:26310628). The variant cosegregates with disease in multiple affected family members and the prevalence of the variant in affected individuals is significantly increased compared with controls (PMID:12207932, PMID:14711881, PMID: 37273706 and in-house data). The following ACMG/AMP criteria were applied in classifying this variant: PM1, PM2, PP1_strong, PP3, PS4_moderate (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jan 23, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	MPZ-related disorders	Blueprint Genetics Accession: SCV007785987.1 First in ClinVar: Sep 22, 2026 Last updated: Sep 22, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 4 Test name: Charcot-Marie-Tooth Neuropathy Panel

Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided	Charcot-Marie-Tooth disease	Inherited Neuropathy Consortium Accession: SCV000928841.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019	Publications: PubMed (1) PubMed: 12207932 Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes Observation 1 Collection method: literature only Allele origin: germline Affected status: yes

Comment:

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.

Comment:

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 13,236 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.

Comment:

This is a nonsynonymous variant in the MPZ gene (OMIM: 159440). Pathogenic variants in this gene have been associated with autosomal dominant Charcot-Marie-Tooth disease type 1B (CMT1B). This variant has been reported in at least 2 unrelated affected individuals (PMID: 12207932, 36203352) (PS4_Moderate) and observed to segregate with disease in at least 3 individuals from one family (PMID: 12207932 ) (PP1). This variant lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the MPZ protein (PM1) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.692) (PP3). This variant has a 0.0009% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as likely pathogenic for autosomal dominant Charcot-Marie-Tooth disease type 1B (CMT1B).

Comment:

The NM_000530.8:c.418T>A missense variant (REVEL score = 0.692) is rare in population database (0.00047% gnomAD-nonUKB v4.1.0) and is located in a cluster of amino acids in the MPZ ex- tracellular domain where substitutions are reported as disease causing (PMID:26310628). The variant cosegregates with disease in multiple affected family members and the prevalence of the variant in affected individuals is significantly increased compared with controls (PMID:12207932, PMID:14711881, PMID: 37273706 and in-house data). The following ACMG/AMP criteria were applied in classifying this variant: PM1, PM2, PP1_strong, PP3, PS4_moderate

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders.	Ek M	Frontiers in neurology	2023	PMID: 37273706
Disease Progression in Charcot-Marie-Tooth Disease Related to MPZ Mutations: A Longitudinal Study.	Fridman V	Annals of neurology	2023	PMID: 36203352
Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene.	Sanmaneechai O	Brain : a journal of neurology	2015	PMID: 26310628
Two novel MPZ mutations in Chinese CMT patients.	Liu L	Journal of the peripheral nervous system : JPNS	2013	PMID: 24028194
[Clinical-genetic correlations in the hereditary motor-sensor neuropathy caused by mutations in the MPZ (P0) gene].	Milovidova TB	Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova	2011	PMID: 22433810
Phenotypic clustering in MPZ mutations.	Shy ME	Brain : a journal of neurology	2004	PMID: 14711881
Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes.	Street VA	Neuromuscular disorders : NMD	2002	PMID: 12207932

Text-mined citations for rs572010627 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 27, 2026