NM_000530.8(MPZ):c.424G>A (p.Val142Ile) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 13, 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:: RCV003741779.1

Allele description [Variation Report for NM_000530.8(MPZ):c.424G>A (p.Val142Ile)]

NM_000530.8(MPZ):c.424G>A (p.Val142Ile)

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.424G>A (p.Val142Ile)

HGVS:

NC_000001.11:g.161306732C>T
NG_008055.1:g.8241G>A
NM_000530.8:c.424G>AMANE SELECT
NM_001315491.2:c.424G>A
NP_000521.2:p.Val142Ile
NP_000521.2:p.Val142Ile
NP_001302420.1:p.Val142Ile
LRG_256t1:c.424G>A
LRG_256:g.8241G>A
LRG_256p1:p.Val142Ile
NC_000001.10:g.161276522C>T
NM_000530.6:c.424G>A

Protein change:

V142I

Molecular consequence:

NM_000530.8:c.424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001315491.2:c.424G>A - 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
SCV004412334	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26310628, 33179255, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004412334

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 13, 2023)

germline

clinical testing

PubMed (3)
[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

Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene.

Sanmaneechai O, Feely S, Scherer SS, Herrmann DN, Burns J, Muntoni F, Li J, Siskind CE, Day JW, Laura M, Sumner CJ, Lloyd TE, Ramchandren S, Shy RR, Grider T, Bacon C, Finkel RS, Yum SW, Moroni I, Piscosquito G, Pareyson D, Reilly MM, et al.

Brain. 2015 Nov;138(Pt 11):3180-92. doi: 10.1093/brain/awv241. Epub 2015 Aug 25.

PubMed [citation]

PMID:: 26310628
PMCID:: PMC4643641

Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan.

Taniguchi T, Ando M, Okamoto Y, Yoshimura A, Higuchi Y, Hashiguchi A, Shiga K, Hayashida A, Hatano T, Ishiura H, Mitsui J, Hattori N, Mizuno T, Nakagawa M, Tsuji S, Takashima H.

Clin Genet. 2021 Mar;99(3):359-375. doi: 10.1111/cge.13881. Epub 2020 Nov 27.

PubMed [citation]

PMID:: 33179255
PMCID:: PMC7898366

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004412334.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Val142 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been observed in individuals with MPZ-related conditions (PMID: 26310628, 33179255; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 not expected to disrupt MPZ protein function. This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 142 of the MPZ protein (p.Val142Ile).

#	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: Feb 28, 2024

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