VCV000208149.9 - ClinVar

NM_000530.8(MPZ):c.499G>A (p.Gly167Arg)

Germline

Classification

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

Pathogenic

2 out of 4 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.499G>A (p.Gly167Arg)

Variation ID: 208149 Accession: VCV000208149.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q23.3 1: 161276204 (GRCh37) [ NCBI UCSC ] 1: 161306414 (GRCh38) [ 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	Oct 5, 2015	Apr 12, 2026	Dec 24, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000530.8:c.499G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000521.2:p.Gly167Arg	missense
NM_001315491.2:c.499G>A	NP_001302420.1:p.Gly167Arg	missense
NC_000001.11:g.161306414C>T
NC_000001.10:g.161276204C>T
NG_008055.1:g.8559G>A
LRG_256:g.8559G>A
LRG_256t1:c.499G>A	LRG_256p1:p.Gly167Arg
	P25189:p.Gly167Arg

... more HGVS ... less HGVS

Protein change

G167R

Other names

Canonical SPDI

NC_000001.11:161306413:C: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.

Links

ClinGen: CA347426 UniProtKB: P25189#VAR_004544 dbSNP: rs121913586 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		-	-	GRCh38 GRCh37	621	648

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.
Charcot-Marie-Tooth disease type 1B	not provided (1)	no classification provided	-	RCV000194294.10
Charcot-Marie-Tooth disease	Uncertain significance (1)	no assertion criteria provided	-	RCV000789484.9
Charcot-Marie-Tooth disease, type I	Pathogenic (1)	criteria provided, single submitter	Dec 24, 2021	RCV001053594.14
Roussy-Lévy syndrome	Pathogenic (1)	criteria provided, single submitter	-	RCV006646104.1

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.
Pathogenic (Dec 24, 2021) 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: SCV001217864.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 10399750‚ 12242557‚ 29687021‚ 7506095 Comment: show This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 167 of the MPZ protein (p.Gly167Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dejerine-Sottas disease (PMID: 7506095, 10399750, 12242557). In at least one individual the variant was observed to be de novo. This variant is also known as p.Gly138Arg. ClinVar contains an entry for this variant (Variation ID: 208149). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MPZ function (PMID: 29687021). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Roussy-Lévy syndrome	Clinical Biomedical Laboratory, Shriners Hospital For Children - Canada Accession: SCV007538886.1 First in ClinVar: Apr 12, 2026 Last updated: Apr 12, 2026	Comment: show This variant is predicted to substitute an glycine residue by an arginine residue in MPZ. This variant is absent in the Genome Aggregation Database (gnomAD v2.1.1), indicating it is very rare. Computational tools (REVEL: 0.71) suggest that the amino acid change is damaging to protein function. The gene is associated with Charcot–Marie–Tooth disease type 1B, which is in accordance with the clinical diagnosis of the proband. This variant has been reported as a cause of Charcot–Marie–Tooth disease type 1B (e.g. PMID 26310628). Based on the ACMG variant interpretation guidelines (criteria PS1, PM2, PM5, PP2), the available evidence supports classification of this variant as pathogenic. (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

Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided	Charcot-Marie-Tooth disease	Inherited Neuropathy Consortium Accession: SCV000928840.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019	Publications: PubMed (1) PubMed: 9452099 Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes Observation 1 Collection method: literature only Allele origin: germline Affected status: yes

not provided (-) N Not contributing to aggregate classification	no classification provided	Charcot-Marie-Tooth disease type 1B	GeneReviews Accession: SCV000243906.2 First in ClinVar: Oct 05, 2015 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1205 BookShelf: NBK1205 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:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 167 of the MPZ protein (p.Gly167Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dejerine-Sottas disease (PMID: 7506095, 10399750, 12242557). In at least one individual the variant was observed to be de novo. This variant is also known as p.Gly138Arg. ClinVar contains an entry for this variant (Variation ID: 208149). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MPZ function (PMID: 29687021). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant is predicted to substitute an glycine residue by an arginine residue in MPZ. This variant is absent in the Genome Aggregation Database (gnomAD v2.1.1), indicating it is very rare. Computational tools (REVEL: 0.71) suggest that the amino acid change is damaging to protein function. The gene is associated with Charcot–Marie–Tooth disease type 1B, which is in accordance with the clinical diagnosis of the proband. This variant has been reported as a cause of Charcot–Marie–Tooth disease type 1B (e.g. PMID 26310628). Based on the ACMG variant interpretation guidelines (criteria PS1, PM2, PM5, PP2), the available evidence supports classification of this variant as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B.	Bai Y	Annals of clinical and translational neurology	2018	PMID: 29687021
Charcot-Marie-Tooth Neuropathy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2015	PMID: 20301384
Dejerine-Sottas neuropathy with multiple nerve roots enlargement and hypomyelination associated with a missense mutation of the transmembrane domain of MPZ/P0.	Simonati A	Journal of neurology	2002	PMID: 12242557
Germline mosaicism of MPZ gene in Dejerine-Sottas syndrome (HMSN III) associated with hereditary stomatocytosis.	Takashima H	Neuromuscular disorders : NMD	1999	PMID: 10399750
Mutation analysis in Charcot-Marie-Tooth disease type 1 (CMT1).	Sorour E	Human mutation	1998	PMID: 9452099
De novo mutation of the myelin P0 gene in Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III).	Hayasaka K	Nature genetics	1993	PMID: 7506095

Text-mined citations for rs121913586 ...

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 Apr 13, 2026