NM_000530.8(MPZ):c.296T>C (p.Ile99Thr) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 16, 2020
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:: RCV000812847.6

Allele description [Variation Report for NM_000530.8(MPZ):c.296T>C (p.Ile99Thr)]

NM_000530.8(MPZ):c.296T>C (p.Ile99Thr)

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.296T>C (p.Ile99Thr)

HGVS:

NC_000001.11:g.161306860A>G
NG_008055.1:g.8113T>C
NM_000530.8:c.296T>CMANE SELECT
NM_001315491.2:c.296T>C
NP_000521.2:p.Ile99Thr
NP_001302420.1:p.Ile99Thr
LRG_256t1:c.296T>C
LRG_256:g.8113T>C
NC_000001.10:g.161276650A>G
NM_000530.6:c.296T>C

Protein change:

I99T

Links:

dbSNP: rs1571819182

NCBI 1000 Genomes Browser:

rs1571819182

Molecular consequence:

NM_000530.8:c.296T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001315491.2:c.296T>C - 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
SCV000953175	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 16, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9888385, 10093067, 26310628, 11080236, 29687021, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000953175

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 16, 2020)

germline

clinical testing

PubMed (6)
[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 in the peripheral myelin genes and associated genes in inherited peripheral neuropathies.

Nelis E, Haites N, Van Broeckhoven C.

Hum Mutat. 1999;13(1):11-28. Review.

PubMed [citation]

PMID:: 9888385

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.

[No authors listed]

Neuromuscul Disord. 1998 Dec;8(8):591-603. No abstract available.

PubMed [citation]

PMID:: 10093067

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000953175.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant has been reported in several individuals affected with Charcot-Marie-Tooth disease, type 1 (PMID: 9888385, 10093067, 26310628) and has been observed to segregate with Charcot-Marie-Tooth disease in a family (PMID: 11080236 ). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change causes retention of the MPZ protein in the endoplasmic reticulum leading to increased protein degradation (PMID: 29687021). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 99 of the MPZ protein (p.Ile99Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine.

#	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 20, 2024

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