VCV000014181.48 - ClinVar

NM_000530.8(MPZ):c.371C>T (p.Thr124Met)

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.

(14)

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.371C>T (p.Thr124Met)

Variation ID: 14181 Accession: VCV000014181.48

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q23.3 1: 161306785 (GRCh38) [ NCBI UCSC ] 1: 161276575 (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	May 3, 2013	Oct 20, 2024	Dec 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000530.8:c.371C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000521.2:p.Thr124Met	missense
NM_001315491.2:c.371C>T	NP_001302420.1:p.Thr124Met	missense
NC_000001.11:g.161306785G>A
NC_000001.10:g.161276575G>A
NG_008055.1:g.8188C>T
LRG_256:g.8188C>T
LRG_256t1:c.371C>T	LRG_256p1:p.Thr124Met
	NP_000521.1:p.Thr134Met
	P25189:p.Thr124Met

... more HGVS ... less HGVS

Protein change

T124M

Other names

Canonical SPDI

NC_000001.11:161306784: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

UniProtKB: P25189#VAR_004529 OMIM: 159440.0016 dbSNP: rs121913595 ClinGen: CA257158 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 2J	Pathogenic (1)	no assertion criteria provided	Jun 15, 2006	RCV000015244.34
Charcot-Marie-Tooth disease type 1B	Pathogenic (2)	no assertion criteria provided	Jun 15, 2006	RCV000015245.33
Charcot-Marie-Tooth disease	Uncertain significance (1)	no assertion criteria provided	-	RCV000192248.11
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 1, 2022	RCV000517355.35
Charcot-Marie-Tooth disease, type I	Pathogenic (1)	criteria provided, single submitter	Dec 22, 2023	RCV000638155.17
Charcot-Marie-Tooth disease dominant intermediate D Charcot-Marie-Tooth disease type 1B Charcot-Marie-Tooth disease type 2I Charcot-Marie-Tooth disease type 2J Charcot-Marie-Tooth disease type 4E Dejerine-Sottas disease Roussy-Lévy syndrome	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763262.10
Charcot-Marie-Tooth disease dominant intermediate D	Pathogenic (2)	criteria provided, single submitter	Jan 1, 2019	RCV001262744.11
Distal hereditary motor neuropathy type 2	Pathogenic (1)	no assertion criteria provided	-	RCV002245981.10
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 11, 2023	RCV002345245.9

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 (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 1B Dejerine-Sottas disease Roussy-Lévy syndrome Charcot-Marie-Tooth disease type 4E Charcot-Marie-Tooth disease type 2I Charcot-Marie-Tooth disease type 2J Charcot-Marie-Tooth disease dominant intermediate D Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893900.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Oct 09, 2020)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000614106.3 First in ClinVar: Dec 19, 2017 Last updated: Sep 19, 2021	Publications: PubMed (12) PubMed: 12911457‚ 19629567‚ 26234237‚ 25720167‚ 15377707‚ 12948789‚ 20461396‚ 10071056‚ 12207153‚ 15159512‚ 11080237‚ 9452091 Comment: This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. This variant occurs as the most … (more) This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. (less)
Pathogenic (Aug 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002520050.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022	Publications: PubMed (10) PubMed: 10835936‚ 16279991‚ 18337304‚ 19629567‚ 19928689‚ 20461396‚ 25720167‚ 26234237‚ 31211173‚ 31827005 Comment: PP1, PM1, PM2, PS3_moderate, PS4
Pathogenic (Dec 22, 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: SCV000759641.8 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (12) PubMed: 28492532‚ 9452091‚ 10923043‚ 12207153‚ 12948789‚ 15159512‚ 16279991‚ 19629567‚ 25720167‚ 26234237‚ 18337304‚ 20461396 Comment: This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 124 of the MPZ protein (p.Thr124Met). … (more) This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 124 of the MPZ protein (p.Thr124Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 9452091, 10923043, 12207153, 12948789, 15159512, 16279991, 19629567, 25720167, 26234237). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14181). 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: 18337304, 20461396). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease dominant intermediate D Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440723.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Pathogenic (Jun 29, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002540333.2 First in ClinVar: Jul 09, 2022 Last updated: Mar 04, 2023	Comment: Identified in multiple unrelated patients with Charcot-Marie-Tooth (Yoshihara et al., 2000; Gallardo et al., 2009; Liu et al., 2013; Bergamin et al., 2014); Published functional … (more) Identified in multiple unrelated patients with Charcot-Marie-Tooth (Yoshihara et al., 2000; Gallardo et al., 2009; Liu et al., 2013; Bergamin et al., 2014); Published functional studies demonstrate a damaging effect (Grandis et al., 2008; Lee et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 15159512, 19928689, 24819634, 18563718, 18337304, 20461396, 19629567, 10835936, 9452091, 25720167, 26234237, 16279991, 24028194, 15377707, 10071056, 34210210, 33825325, 22820753, 20301384, 16775239, 12911457, 31827005, 30018047, 29516875, 10329755, 25802885, 29687021, 31211173, 12948789, 12207153, 10764043, 26310628, 10923043) (less)
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002623128.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (17) PubMed: 10071056‚ 10329755‚ 10764043‚ 10835936‚ 10923043‚ 15377707‚ 16775239‚ 18337304‚ 20461396‚ 24819634‚ 26234237‚ 29687021‚ 31211173‚ 33179255‚ 33825325‚ 34210210‚ 36350884 Comment: The c.371C>T (p.T124M) alteration is located in exon 3 (coding exon 3) of the MPZ gene. This alteration results from a C to T substitution … (more) The c.371C>T (p.T124M) alteration is located in exon 3 (coding exon 3) of the MPZ gene. This alteration results from a C to T substitution at nucleotide position 371, causing the threonine (T) at amino acid position 124 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in the heterozygous state in multiple individuals with adult-onset neuropathy and cosegregates with disease in several families (Bisogni, 2022; Kim, 2021; Taniguchi, 2020; Hsu, 2019; Tokuda, 2015; Bergamin, 2014; Triggs, 2006; Kurihara, 2004; Baloh, 2004; Yoshihara, 2000; Misu, 2000; Senderek, 2000; De Jonghe, 1999; Chapon, 1999; Schiavon, 1998). This amino acid position is highly conserved in available vertebrate species. Multiple functional studies indicate that this alteration does not alter trafficking of MPZ to the plasma membrane, but disrupts MPZ glycosylation and may impair adhesion and myelin stability (Grandis, 2008; Lee, 2010; Bai, 2018; Shackleford, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jul 01, 2022)	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: SCV001249783.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: MPZ: PM1, PM2, PP1:Moderate, PS3:Moderate, PS4:Moderate Number of individuals with the variant: 2
Pathogenic (Jun 15, 2006)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, TYPE 1B Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035504.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 14, 2018	Publications: PubMed (7) PubMed: 9452091‚ 10071056‚ 10329755‚ 11080237‚ 10764043‚ 15159512‚ 16775239 Comment on evidence: In a man with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Schiavon et al. (1998) identified a 371C-T transition in exon 3 of the MPZ gene, … (more) In a man with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Schiavon et al. (1998) identified a 371C-T transition in exon 3 of the MPZ gene, resulting in a thr124-to-met (T124M) substitution. The patient had a relatively mild clinical course, with onset of generalized asthenia at age 42 years and a slightly decreased motor NCV of 37 m/s. In 7 Charcot-Marie-Tooth families and in 2 isolated CMT patients of Belgian ancestry, De Jonghe et al. (1999) found the T124M mutation. Allele-sharing analysis of markers flanking the MPZ gene indicated that all patients with the T124M mutation had 1 common ancestor. The mutation was associated with a clinically distinct phenotype characterized by axonal involvement, late onset, marked sensory abnormalities, and, in some families, deafness and pupillary abnormalities (CMT2J; 607736). Nerve conduction velocities of the motor median nerve varied from less than 38 m/s to normal values in these patients. Clusters of remyelinating axons in the sural nerve biopsy demonstrated an axonal involvement, with axonal regeneration. Phenotype/genotype correlations in 30 patients with the mutation indicated that, based on nerve conduction velocity criteria, these patients were difficult to classify as CMT1 or CMT2. De Jonghe et al. (1999) concluded that CMT patients with slightly reduced or nearly normal nerve conduction velocity should be screened for MPZ mutations, particularly when additional clinical features such as marked sensory disturbances, pupillary abnormalities, or deafness are also present. Chapon et al. (1999) and Misu et al. (2000) likewise found a distinct CMT type 2 axonal phenotype with pupillary anomalies, deafness, and sensory abnormalities associated with the T124M mutation. Senderek et al. (2000) suggested that T124M reflects a mutation hotspot. Baloh et al. (2004) reported a family in which multiple members spanning 3 generations had severe chronic recurring coughing spasms, beginning in their teens and lasting for 20 to 30 minutes and ending in retching or vomiting. All affected members had tonic pupils and most developed late-onset axonal peripheral neuropathy. The features resembled CMT with hearing loss and pupillary abnormalities reported by De Jonghe et al. (1999) and Misu et al. (2000), but hearing loss was not a feature in this family. The proband also reported gastrointestinal symptoms diagnosed as irritable bowel syndrome, occasional urinary incontinence, and erectile dysfunction. The proband and his affected sister and mother were heterozygous for the T124M mutation; 4 unaffected family members tested did not have the mutation. Baloh et al. (2004) concluded that the T124M mutation results in dysfunction of the autonomic nervous system. Triggs et al. (2006) described a family with the characteristic features of CMT2J and the T124M mutation. (less)
Pathogenic (Jun 15, 2006)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, TYPE 2J Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035503.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 14, 2018	Publications: PubMed (7) PubMed: 9452091‚ 10071056‚ 10329755‚ 11080237‚ 10764043‚ 15159512‚ 16775239 Comment on evidence: In a man with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Schiavon et al. (1998) identified a 371C-T transition in exon 3 of the MPZ gene, … (more) In a man with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Schiavon et al. (1998) identified a 371C-T transition in exon 3 of the MPZ gene, resulting in a thr124-to-met (T124M) substitution. The patient had a relatively mild clinical course, with onset of generalized asthenia at age 42 years and a slightly decreased motor NCV of 37 m/s. In 7 Charcot-Marie-Tooth families and in 2 isolated CMT patients of Belgian ancestry, De Jonghe et al. (1999) found the T124M mutation. Allele-sharing analysis of markers flanking the MPZ gene indicated that all patients with the T124M mutation had 1 common ancestor. The mutation was associated with a clinically distinct phenotype characterized by axonal involvement, late onset, marked sensory abnormalities, and, in some families, deafness and pupillary abnormalities (CMT2J; 607736). Nerve conduction velocities of the motor median nerve varied from less than 38 m/s to normal values in these patients. Clusters of remyelinating axons in the sural nerve biopsy demonstrated an axonal involvement, with axonal regeneration. Phenotype/genotype correlations in 30 patients with the mutation indicated that, based on nerve conduction velocity criteria, these patients were difficult to classify as CMT1 or CMT2. De Jonghe et al. (1999) concluded that CMT patients with slightly reduced or nearly normal nerve conduction velocity should be screened for MPZ mutations, particularly when additional clinical features such as marked sensory disturbances, pupillary abnormalities, or deafness are also present. Chapon et al. (1999) and Misu et al. (2000) likewise found a distinct CMT type 2 axonal phenotype with pupillary anomalies, deafness, and sensory abnormalities associated with the T124M mutation. Senderek et al. (2000) suggested that T124M reflects a mutation hotspot. Baloh et al. (2004) reported a family in which multiple members spanning 3 generations had severe chronic recurring coughing spasms, beginning in their teens and lasting for 20 to 30 minutes and ending in retching or vomiting. All affected members had tonic pupils and most developed late-onset axonal peripheral neuropathy. The features resembled CMT with hearing loss and pupillary abnormalities reported by De Jonghe et al. (1999) and Misu et al. (2000), but hearing loss was not a feature in this family. The proband also reported gastrointestinal symptoms diagnosed as irritable bowel syndrome, occasional urinary incontinence, and erectile dysfunction. The proband and his affected sister and mother were heterozygous for the T124M mutation; 4 unaffected family members tested did not have the mutation. Baloh et al. (2004) concluded that the T124M mutation results in dysfunction of the autonomic nervous system. Triggs et al. (2006) described a family with the characteristic features of CMT2J and the T124M mutation. (less)
Uncertain significance (-)	no assertion criteria provided Method: literature only	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Inherited Neuropathy Consortium Accession: SCV000929509.1 First in ClinVar: Jul 29, 2019 Last updated: Jul 29, 2019	Publications: PubMed (1) PubMed: 9452091
Likely pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Charcot-Marie-Tooth disease dominant intermediate D Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001759992.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Distal hereditary motor neuropathy type 2 Affected status: yes Allele origin: inherited	Chongqing Key Laboratory of Neurology, First Affiliated Hospital of Chongqing Medical University Accession: SCV002512139.1 First in ClinVar: May 24, 2022 Last updated: May 24, 2022	Publications: DOI: 10.1111/ene.14260 DOI: 10.1111/ene.14260 Clinical Features: Muscle weakness (present) , Unsteady gait (present) , Paresthesia (present) , Distal amyotrophy (present)
not provided (-)	no classification provided Method: literature only	Charcot-Marie-Tooth disease type 1B Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000057834.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1205 BookShelf: NBK1205
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Comment:

This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure.

Comment:

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 124 of the MPZ protein (p.Thr124Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 9452091, 10923043, 12207153, 12948789, 15159512, 16279991, 19629567, 25720167, 26234237). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14181). 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: 18337304, 20461396). For these reasons, this variant has been classified as Pathogenic.

Comment:

Identified in multiple unrelated patients with Charcot-Marie-Tooth (Yoshihara et al., 2000; Gallardo et al., 2009; Liu et al., 2013; Bergamin et al., 2014); Published functional studies demonstrate a damaging effect (Grandis et al., 2008; Lee et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 15159512, 19928689, 24819634, 18563718, 18337304, 20461396, 19629567, 10835936, 9452091, 25720167, 26234237, 16279991, 24028194, 15377707, 10071056, 34210210, 33825325, 22820753, 20301384, 16775239, 12911457, 31827005, 30018047, 29516875, 10329755, 25802885, 29687021, 31211173, 12948789, 12207153, 10764043, 26310628, 10923043)

Comment:

The c.371C>T (p.T124M) alteration is located in exon 3 (coding exon 3) of the MPZ gene. This alteration results from a C to T substitution at nucleotide position 371, causing the threonine (T) at amino acid position 124 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in the heterozygous state in multiple individuals with adult-onset neuropathy and cosegregates with disease in several families (Bisogni, 2022; Kim, 2021; Taniguchi, 2020; Hsu, 2019; Tokuda, 2015; Bergamin, 2014; Triggs, 2006; Kurihara, 2004; Baloh, 2004; Yoshihara, 2000; Misu, 2000; Senderek, 2000; De Jonghe, 1999; Chapon, 1999; Schiavon, 1998). This amino acid position is highly conserved in available vertebrate species. Multiple functional studies indicate that this alteration does not alter trafficking of MPZ to the plasma membrane, but disrupts MPZ glycosylation and may impair adhesion and myelin stability (Grandis, 2008; Lee, 2010; Bai, 2018; Shackleford, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is 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
A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication.	Shackleford G	PLoS genetics	2022	PMID: 36350884
Thr124Met myelin protein zero mutation mimicking motor neuron disease.	Bisogni G	Amyotrophic lateral sclerosis & frontotemporal degeneration	2022	PMID: 34210210
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
Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan.	Taniguchi T	Clinical genetics	2021	PMID: 33179255
Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease.	Cortese A	Neurology	2020	PMID: 31827005
Mutation spectrum of Charcot-Marie-Tooth disease among the Han Chinese in Taiwan.	Hsu YH	Annals of clinical and translational neurology	2019	PMID: 31211173
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
Parasympathetic Dominant Autonomic Dysfunction in Charcot-Marie-Tooth Disease Type 2J with the MPZ Thr124Met Mutation.	Tokuda N	Internal medicine (Tokyo, Japan)	2015	PMID: 26234237
Charcot-Marie-Tooth Neuropathy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2015	PMID: 20301384
A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype.	Leal A	Revista de biologia tropical	2014	PMID: 25720167
Mutation analysis of MFN2, GJB1, MPZ and PMP22 in Italian patients with axonal Charcot-Marie-Tooth disease.	Bergamin G	Neuromolecular medicine	2014	PMID: 24819634
Cellular characterization of MPZ mutations presenting with diverse clinical phenotypes.	Lee YC	Journal of neurology	2010	PMID: 20461396
[Predominant parasympathetic involvement in a patient with Charcot-Marie-Tooth disease caused by the MPZ Thr124Met mutation].	Nakamura N	Rinsho shinkeigaku = Clinical neurology	2009	PMID: 19928689
Charcot–Marie–Tooth disease type 2J with MPZ Thr124Met mutation: clinico-electrophysiological and MRI study of a family.	Gallardo E	Journal of neurology	2009	PMID: 19629567
Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations.	Grandis M	Human molecular genetics	2008	PMID: 18337304
Case records of the Massachusetts General Hospital. Case 18-2006. A 57-year-old woman with numbness and weakness of the feet and legs.	Triggs WJ	The New England journal of medicine	2006	PMID: 16775239
Charcot-Marie-Tooth disease due to the Thr124Met mutation in the myelin protein zero gene associated with multiple sclerosis.	Rajabally YA	Journal of the peripheral nervous system : JPNS	2005	PMID: 16279991
Charcot-Marie-Tooth families in Japan with MPZ Thr124Met mutation.	Kurihara S	Journal of neurology, neurosurgery, and psychiatry	2004	PMID: 15377707
Chronic cough due to Thr124Met mutation in the peripheral myelin protein zero (MPZ gene).	Baloh RH	Neurology	2004	PMID: 15159512
Autonomic and respiratory dysfunction in Charcot-Marie-Tooth disease due to Thr124Met mutation in the myelin protein zero gene.	Stojkovic T	Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology	2003	PMID: 12948789
Axonal and demyelinating forms of the MPZ Thr124Met mutation.	Kurihara S	Acta neurologica Scandinavica	2003	PMID: 12911457
An epidemiological genetic study of Charcot-Marie-Tooth disease in Western Japan.	Kurihara S	Neuroepidemiology	2002	PMID: 12207153
An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (Thr124Met or Asp75Val).	Misu K	Journal of neurology, neurosurgery, and psychiatry	2000	PMID: 11080237
Mutations in the peripheral myelin protein zero and connexin32 genes detected by non-isotopic RNase cleavage assay and their phenotypes in Japanese patients with Charcot-Marie-Tooth disease.	Yoshihara T	Human mutation	2000	PMID: 10923043
[Two families of Charcot-Marie-Tooth disease with Adie's pupil, axonal neuropahy and the Thr124Met mutation in the peripheral myelin protein zero gene].	Misu K	Rinsho shinkeigaku = Clinical neurology	2000	PMID: 10835936
Charcot-Marie-Tooth neuropathy type 2 and P0 point mutations: two novel amino acid substitutions (Asp61Gly; Tyr119Cys) and a possible "hotspot" on Thr124Met.	Senderek J	Brain pathology (Zurich, Switzerland)	2000	PMID: 10764043
Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene.	Chapon F	Journal of neurology, neurosurgery, and psychiatry	1999	PMID: 10329755
The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot-Marie-Tooth phenotype.	De Jonghe P	Brain : a journal of neurology	1999	PMID: 10071056
Mutations of the same sequence of the myelin P0 gene causing two different phenotypes.	Schiavon F	Human mutation	1998	PMID: 9452091
-	-	-	-	DOI: 10.1111/ene.14260
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Text-mined citations for rs121913595 ...

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Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000530.8(MPZ):c.371C>T (p.Thr124Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913595 ...