VCV000014188.30 - ClinVar

NM_000530.8(MPZ):c.233C>T (p.Ser78Leu)

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.

(8)

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.233C>T (p.Ser78Leu)

Variation ID: 14188 Accession: VCV000014188.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q23.3 1: 161307259 (GRCh38) [ NCBI UCSC ] 1: 161277049 (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	Dec 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000530.8:c.233C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000521.2:p.Ser78Leu	missense
NM_001315491.2:c.233C>T	NP_001302420.1:p.Ser78Leu	missense
NC_000001.11:g.161307259G>A
NC_000001.10:g.161277049G>A
NG_008055.1:g.7714C>T
LRG_256:g.7714C>T
LRG_256t1:c.233C>T	LRG_256p1:p.Ser78Leu
	P25189:p.Ser78Leu

... more HGVS ... less HGVS

Protein change

S78L

Other names

S49L

Canonical SPDI

NC_000001.11:161307258: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.

Links

ClinGen: CA123805 UniProtKB: P25189#VAR_004512 OMIM: 159440.0023 dbSNP: rs121913601 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, WITH FOCALLY FOLDED MYELIN SHEATHS	Pathogenic (1)	no assertion criteria provided	Sep 1, 2000	RCV000015252.24
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 1, 2023	RCV000436362.25
Charcot-Marie-Tooth disease, type I	Pathogenic (1)	criteria provided, single submitter	Dec 14, 2023	RCV000546842.9
Charcot-Marie-Tooth disease	Pathogenic (1)	criteria provided, single submitter	-	RCV001173691.2

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 (Sep 15, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000334765.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MPZ Number of individuals with the variant: 1 Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001336801.1 First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020
Pathogenic (Dec 01, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000255796.3 First in ClinVar: Oct 19, 2015 Last updated: Jan 26, 2024	Publications: PubMed (13) PubMed: 29687021‚ 18347322‚ 33825325‚ 32376792‚ 10965800‚ 18422810‚ 9187667‚ 10093067‚ 9633821‚ 11437164‚ 11835375‚ 12497641‚ 7527371 Comment: This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant Charcot-Marie-Tooth disease and segregates with disease in multiple families. … (more) This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant Charcot-Marie-Tooth disease and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations. In some published literature, this variant is referred to as p.Ser49Leu. The variant is located in a region that is considered important for protein function and/or structure. (less)
Pathogenic (Dec 14, 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: SCV000636239.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 7527371‚ 9633821‚ 10965800‚ 18347322‚ 12707985 Comment: This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 78 of the MPZ protein (p.Ser78Leu). … (more) This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 78 of the MPZ protein (p.Ser78Leu). 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 type I (PMID: 7527371, 9633821, 10965800, 18347322). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14188). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Ser78 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7527371, 9633821, 12707985, 18347322; Invitae). 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)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal unknown) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446790.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Polyneuropathy (present) Sex: female
Pathogenic (Jan 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000521268.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that … (more) Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26310628, 26135405, 26481167, 25429913, 19691535, 19293842, 7527371, 19259128, 11545686, 10965800, 11437164, 9633821, 9187667, 11835375, 12497641, 10093067, 7550231, 18347322, 26406915, 18422810, 29687021, 32376792, 33825325, 12707985, 9883862, 20461396) (less)
Pathogenic (Jun 01, 2023)	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: SCV004009899.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: MPZ: PS4, PM1, PM2, PM5, PP1 Number of individuals with the variant: 1
Pathogenic (Sep 01, 2000)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, TYPE 1B, WITH FOCALLY FOLDED MYELIN SHEATHS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035511.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 14, 2018	Publications: PubMed (1) PubMed: 10965800 Comment on evidence: In 2 pedigrees with a late-onset, relatively mild form of Charcot-Marie-Tooth disease 1B with focally folded myelin sheaths (CMT1B; 118200), Fabrizi et al. (2000) identified … (more) In 2 pedigrees with a late-onset, relatively mild form of Charcot-Marie-Tooth disease 1B with focally folded myelin sheaths (CMT1B; 118200), Fabrizi et al. (2000) identified a heterozygous 233C-T transition in exon 2 of the MPZ gene, resulting in a ser49-to-leu (S49L) substitution in the extracellular domain of the protein. Pathology showed a characteristic demyelinating process, but also revealed irregular myelin outfoldings and infoldings and tomacula. Fabrizi et al. (2000) noted that the mutation exchanges a polar amino acid with a hydrophobic amino acid, and suggested that the change would result in myelin uncompaction which could lead to out- or infoldings. The authors also noted that myelin outfoldings have been described in other CMT patients with mutations in MPZ, EGR2 (129010.0004), and PMP22 (601097.0016), and that the finding is not restricted to CMT4B (see CMT4B1; 601382). (less)

Comment:

This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant Charcot-Marie-Tooth disease and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations. In some published literature, this variant is referred to as p.Ser49Leu. The variant is located in a region that is considered important for protein function and/or structure.

Comment:

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 78 of the MPZ protein (p.Ser78Leu). 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 type I (PMID: 7527371, 9633821, 10965800, 18347322). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14188). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Ser78 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7527371, 9633821, 12707985, 18347322; Invitae). 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:

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26310628, 26135405, 26481167, 25429913, 19691535, 19293842, 7527371, 19259128, 11545686, 10965800, 11437164, 9633821, 9187667, 11835375, 12497641, 10093067, 7550231, 18347322, 26406915, 18422810, 29687021, 32376792, 33825325, 12707985, 9883862, 20461396)

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
Genetic and clinical spectrums in Korean Charcot-Marie-Tooth disease patients with myelin protein zero mutations.	Kim HJ	Molecular genetics & genomic medicine	2021	PMID: 33825325
Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients.	Volodarsky M	Journal of medical genetics	2021	PMID: 32376792
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 disease type 1B: marked phenotypic variation of the Ser78Leu mutation in five Italian families.	Mazzeo A	Acta neurologica Scandinavica	2008	PMID: 18422810
Uniparental disomy of chromosome 1 causing concurrent Charcot-Marie-Tooth and Gaucher disease Type 3.	Benko WS	Neurology	2008	PMID: 18347322
Clinical and genetic analysis of CMT1B in a Nigerian family.	Kakar R	Muscle & nerve	2003	PMID: 12707985
Novel mutations in the Charcot-Marie-Tooth disease genes PMP22, MPZ, and GJB1.	Huehne K	Human mutation	2003	PMID: 12497641
Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.	Boerkoel CF	Annals of neurology	2002	PMID: 11835375
Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity.	Young P	Journal of neurology	2001	PMID: 11437164
Focally folded myelin in Charcot-Marie-Tooth neuropathy type 1B with Ser49Leu in the myelin protein zero.	Fabrizi GM	Acta neuropathologica	2000	PMID: 10965800
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
Spectrum of mutations in Finnish patients with Charcot-Marie-Tooth disease and related neuropathies.	Silander K	Human mutation	1998	PMID: 9633821
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
Rapid screening of myelin genes in CMT1 patients by SSCP analysis: identification of new mutations and polymorphisms in the P0 gene.	Nelis E	Human genetics	1994	PMID: 7527371
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MPZ	-	-	-	-
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Text-mined citations for rs121913601 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000530.8(MPZ):c.233C>T (p.Ser78Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913601 ...