NM_000530.8(MPZ):c.371C>T (p.Thr124Met) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 22, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000638155.16

Allele description [Variation Report for NM_000530.8(MPZ):c.371C>T (p.Thr124Met)]

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

Gene:

MPZ:myelin protein zero [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q23.3

Genomic location:

Preferred name:

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

HGVS:

NC_000001.11:g.161306785G>A
NG_008055.1:g.8188C>T
NM_000530.8:c.371C>TMANE SELECT
NM_001315491.2:c.371C>T
NP_000521.2:p.Thr124Met
NP_000521.2:p.Thr124Met
NP_001302420.1:p.Thr124Met
LRG_256t1:c.371C>T
LRG_256:g.8188C>T
LRG_256p1:p.Thr124Met
NC_000001.10:g.161276575G>A
NM_000530.5:c.401C>T
NM_000530.6:c.371C>T
NM_000530.7:c.371C>T
NP_000521.1:p.Thr134Met
P25189:p.Thr124Met

Protein change:

T124M; THR124MET

Links:

UniProtKB: P25189#VAR_004529; OMIM: 159440.0016; dbSNP: rs121913595

NCBI 1000 Genomes Browser:

rs121913595

Molecular consequence:

NM_000530.8:c.371C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001315491.2:c.371C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease, type I (CMT1)
Synonyms:: Charcot-Marie-Tooth Neuropathy Type 1; Hereditary Motor and Sensory Neuropathy 1; Charcot-Marie-Tooth, Type 1
Identifiers:: MONDO: MONDO:0019011; MedGen: C0751036

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000759641	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 22, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 9452091, 10923043, 12207153, 12948789, 15159512, 16279991, 19629567, 25720167, 26234237, 18337304, 20461396, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000759641

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 22, 2023)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations of the same sequence of the myelin P0 gene causing two different phenotypes.

Schiavon F, Rampazzo A, Merlini L, Angelini C, Mostacciuolo ML.

Hum Mutat. 1998;Suppl 1:S217-9. No abstract available.

PubMed [citation]

PMID:: 9452091

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, Yamamoto M, Doyu M, Mis KI, Hattori N, Hasegawa Y, Mokuno K, Mitsuma T, Sobue G.

Hum Mutat. 2000 Aug;16(2):177-8.

PubMed [citation]

PMID:: 10923043

See all PubMed Citations (12)

Details of each submission

From Invitae, SCV000759641.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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