NM_000530.8(MPZ):c.331T>C (p.Ser111Pro) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 19, 2022
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:: RCV000549580.6

Allele description [Variation Report for NM_000530.8(MPZ):c.331T>C (p.Ser111Pro)]

NM_000530.8(MPZ):c.331T>C (p.Ser111Pro)

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.331T>C (p.Ser111Pro)

HGVS:

NC_000001.11:g.161306825A>G
NG_008055.1:g.8148T>C
NM_000530.8:c.331T>CMANE SELECT
NM_001315491.2:c.331T>C
NP_000521.2:p.Ser111Pro
NP_001302420.1:p.Ser111Pro
LRG_256t1:c.331T>C
LRG_256:g.8148T>C
NC_000001.10:g.161276615A>G
NM_000530.6:c.331T>C

Protein change:

S111P

Links:

dbSNP: rs1553259664

NCBI 1000 Genomes Browser:

rs1553259664

Molecular consequence:

NM_000530.8:c.331T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001315491.2:c.331T>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
SCV000636245	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 19, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 33179255, 29687021, 19293842, 25429913, 26310628, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000636245

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 19, 2022)

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

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

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B.

Bai Y, Wu X, Brennan KM, Wang DS, D'Antonio M, Moran J, Svaren J, Shy ME.

Ann Clin Transl Neurol. 2018 Apr;5(4):445-455. doi: 10.1002/acn3.543.

PubMed [citation]

PMID:: 29687021
PMCID:: PMC5899917

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000636245.4

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

Description

This missense change has been observed in individual(s) with Charcot‚ÄìMarie‚ÄìTooth disease type 1B (CMT1B) and/or inherited peripheral neuropathy (PMID: 26310628, 33179255). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 111 of the MPZ protein (p.Ser111Pro). ClinVar contains an entry for this variant (Variation ID: 462794). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MPZ function (PMID: 29687021). This variant disrupts the p.Ser111 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19293842, 25429913, 26310628). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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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