VCV000014175.23 - ClinVar

NM_000530.8(MPZ):c.292C>T (p.Arg98Cys)

Germline

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.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000530.8(MPZ):c.292C>T (p.Arg98Cys)

Variation ID: 14175 Accession: VCV000014175.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q23.3 1: 161306864 (GRCh38) [ NCBI UCSC ] 1: 161276654 (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	Oct 19, 2015	Oct 20, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000530.8:c.292C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000521.2:p.Arg98Cys	missense
NM_001315491.2:c.292C>T	NP_001302420.1:p.Arg98Cys	missense
NC_000001.11:g.161306864G>A
NC_000001.10:g.161276654G>A
NG_008055.1:g.8109C>T
LRG_256:g.8109C>T
LRG_256t1:c.292C>T	LRG_256p1:p.Arg98Cys
	P25189:p.Arg98Cys

... more HGVS ... less HGVS

Protein change

R98C

Other names

Canonical SPDI

NC_000001.11:161306863:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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) 0.00001

Links

ClinGen: CA257152 UniProtKB: P25189#VAR_004518 OMIM: 159440.0010 dbSNP: rs121913590 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	647	682

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	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jun 5, 2022	RCV000015238.32
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000237048.13
Charcot-Marie-Tooth disease, type I	Pathogenic (1)	criteria provided, single submitter	Nov 24, 2023	RCV000548074.12

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.	More information 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 (Jun 06, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000292963.12 First in ClinVar: Jul 25, 2016 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect; R98C results in reduced transport of the MPZ protein to the plasma membrane (Lee et al., 2010; Saporta … (more) Published functional studies demonstrate a damaging effect; R98C results in reduced transport of the MPZ protein to the plasma membrane (Lee et al., 2010; Saporta et al., 2012).; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 12477701, 23250879, 9168174, 9187667, 20461396, 19293842, 8816708, 8797476, 17172621, 10093067, 8644725, 21840889, 28704293, 29687021, 15050444, 10207934, 31211173, 31827005, 33825325, 26310628, 24077912, 22689911) (less)
Pathogenic (Jun 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 1B Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807071.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 strong, PP3 supporting Number of individuals with the variant: 1 Clinical Features: Delayed ability to walk (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Delayed ability to sit (present) , Generalized … (more) Delayed ability to walk (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Delayed ability to sit (present) , Generalized hypotonia (present) , Delayed ability to stand (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004704293.8 First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024	Comment: MPZ: PS2, PM1, PM2, PM5, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (Nov 06, 2013)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	Charcot-Marie-Tooth disease, type IB (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000255799.2 First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015	Publications: PubMed (14) PubMed: 8797476‚ 8816708‚ 9187667‚ 11438991‚ 12477701‚ 20461396‚ 21840889‚ 22689911‚ 17172621‚ 19293842‚ 23250879‚ 9168174‚ 10093067‚ 8644725
Pathogenic (May 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 1B Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001521544.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Nov 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease, type I Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000636242.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 8644725‚ 8797476‚ 9168174‚ 20461396‚ 21840889‚ 22689911 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 98 of the MPZ protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 98 of the MPZ protein (p.Arg98Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease and Dejerine-Sottas syndrome (PMID: 8644725, 8797476, 9168174, 20461396, 21840889). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14175). 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) performed at Invitae indicates that this missense variant is expected to disrupt MPZ protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MPZ function (PMID: 20461396, 22689911). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 01, 1996)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, TYPE 1B Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035497.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 14, 2018	Publications: PubMed (2) PubMed: 8644725‚ 7688964 Comment on evidence: Among 20 unrelated French Charcot-Marie-Tooth disease type 1B (CMT1B; 118200) patients without 17p11.2 duplications, Rouger et al. (1996) found 3 different mutations at codon 98. … (more) Among 20 unrelated French Charcot-Marie-Tooth disease type 1B (CMT1B; 118200) patients without 17p11.2 duplications, Rouger et al. (1996) found 3 different mutations at codon 98. No other mutation in exon 3 of the MPZ gene was detected. The mutation was demonstrated to be de novo in 1 of the cases and suspected of being de novo in the other 2, suggesting that mutations occur with a high rate at codon 98. In 1 patient an arg98-to-pro (R98P; 159440.0009) mutation was caused by a 293G-C transversion, whereas in another patient an arg98-to-cys substitution (R98C) was caused by a 292C-T transition. The third mutation was a 293G-A transition, resulting in an arg98-to-his substitution (R98H; 159440.0011). Rouger et al. (1996) noted that this mutation had previously been reported in a Japanese family by Hayasaka et al. (1993). The patient with the R98C mutation showed a more severe clinical and electrophysiologic phenotype than the others with a codon 98 mutation, partly compatible with Dejerine-Sottas syndrome with very early onset (1 year), and a very low nerve conduction velocity, but only mild functional disability at age 8 years. All 3 mutations in codon 98 implied a C-to-T transition (1 on the sense and 2 on the antisense strand), suggesting that they may result from the deamination of a methylcytosine to a thymine. The authors stated that this could explain the high rate of mutations on codon 98. The R98H mutation, characterized by direct sequencing in 2 cases, was not detected by the SSCP technique. Since SSCP analysis was used as the initial screening technique in most previous studies, the frequency of mutations at codon 98 may have been underestimated. The 3 codon 98 mutations represented 20% of the CMT1 patients without duplications and probably a much higher proportion of those with MPZ mutations. These mutations can be picked up by CfoI restriction of exon 3 of the MPZ gene; this approach should be the first step in screening CMT1 patients without duplications. (less)

Comment:

Published functional studies demonstrate a damaging effect; R98C results in reduced transport of the MPZ protein to the plasma membrane (Lee et al., 2010; Saporta et al., 2012).; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 12477701, 23250879, 9168174, 9187667, 20461396, 19293842, 8816708, 8797476, 17172621, 10093067, 8644725, 21840889, 28704293, 29687021, 15050444, 10207934, 31211173, 31827005, 33825325, 26310628, 24077912, 22689911)

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 98 of the MPZ protein (p.Arg98Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease and Dejerine-Sottas syndrome (PMID: 8644725, 8797476, 9168174, 20461396, 21840889). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14175). 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) performed at Invitae indicates that this missense variant is expected to disrupt MPZ protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MPZ function (PMID: 20461396, 22689911). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice.	Patzkó A	Brain : a journal of neurology	2012	PMID: 23250879
MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B.	Saporta MA	Brain : a journal of neurology	2012	PMID: 22689911
Genetic spectrum of hereditary neuropathies with onset in the first year of life.	Baets J	Brain : a journal of neurology	2011	PMID: 21840889
Cellular characterization of MPZ mutations presenting with diverse clinical phenotypes.	Lee YC	Journal of neurology	2010	PMID: 20461396
Clinical features and molecular modelling of novel MPZ mutations in demyelinating and axonal neuropathies.	Mandich P	European journal of human genetics : EJHG	2009	PMID: 19293842
Effect of an R69C mutation in the myelin protein zero gene on myelination and ion channel subtypes.	Bai Y	Archives of neurology	2006	PMID: 17172621
Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients.	Hattori N	Brain : a journal of neurology	2003	PMID: 12477701
Charcot-Marie-Tooth disease type I and related demyelinating neuropathies: Mutation analysis in a large cohort of Italian families.	Mostacciuolo ML	Human mutation	2001	PMID: 11438991
3rd workshop of the European CMT consortium: 54th ENMC International Workshop on genotype/phenotype correlations in Charcot-Marie-Tooth type 1 and hereditary neuropathy with liability to pressure palsies 28-30 November 1997, Naarden, The Netherlands.	-	Neuromuscular disorders : NMD	1998	PMID: 10093067
Mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies.	Bort S	Human genetics	1997	PMID: 9187667
De novo mutation (Arg98-->Cys) of the myelin P0 gene and uncompaction of the major dense line of the myelin sheath in a severe variant of Charcot-Marie-Tooth disease type 1B.	Komiyama A	Journal of the neurological sciences	1997	PMID: 9168174
Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination.	Warner LE	Neuron	1996	PMID: 8816708
Two divergent types of nerve pathology in patients with different P0 mutations in Charcot-Marie-Tooth disease.	Gabreëls-Festen AA	Neurology	1996	PMID: 8797476
High frequency of mutations in codon 98 of the peripheral myelin protein P0 gene in 20 French CMT1 patients.	Rouger H	American journal of human genetics	1996	PMID: 8644725
Mutation of the myelin P0 gene in Charcot-Marie-tooth neuropathy type 1.	Hayasaka K	Biochemical and biophysical research communications	1993	PMID: 7688964
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Text-mined citations for rs121913590 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000530.8(MPZ):c.292C>T (p.Arg98Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913590 ...