NM_000530.8(MPZ):c.670G>T (p.Asp224Tyr) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 15, 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:: RCV000700463.12

Allele description [Variation Report for NM_000530.8(MPZ):c.670G>T (p.Asp224Tyr)]

NM_000530.8(MPZ):c.670G>T (p.Asp224Tyr)

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.670G>T (p.Asp224Tyr)

Other names:

D195Y

HGVS:

NC_000001.11:g.161305953C>A
NG_008055.1:g.9020G>T
NM_000530.8:c.670G>TMANE SELECT
NM_001315491.2:c.670G>T
NP_000521.2:p.Asp224Tyr
NP_001302420.1:p.Asp224Tyr
LRG_256t1:c.670G>T
LRG_256:g.9020G>T
NC_000001.10:g.161275743C>A
NM_000530.5:c.700G>T
NM_000530.6:c.670G>T
P25189:p.Asp224Tyr

Note:

NCBI staff provided an HGVS expression for allelic variant 159440.0036 from the sequence reported in Figure 3 of the paper by Fabrizi et al., 2006 (PubMed 16488608).

Protein change:

D224Y; ASP195TYR

Links:

UniProtKB: P25189#VAR_054397; OMIM: 159440.0036; dbSNP: rs267607247

NCBI 1000 Genomes Browser:

rs267607247

Molecular consequence:

NM_000530.8:c.670G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001315491.2:c.670G>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
SCV000829220	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 15, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16488608, 19259128, 19882637, 21149811, 27088055, 31173589, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000829220

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 15, 2023)

germline

clinical testing

PubMed (7)
[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

Gene dosage sensitivity of a novel mutation in the intracellular domain of P0 associated with Charcot-Marie-Tooth disease type 1B.

Fabrizi GM, Pellegrini M, Angiari C, Cavallaro T, Morini A, Taioli F, Cabrini I, Orrico D, Rizzuto N.

Neuromuscul Disord. 2006 Mar;16(3):183-7. Epub 2006 Feb 20.

PubMed [citation]

PMID:: 16488608

Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations.

Miltenberger-Miltenyi G, Schwarzbraun T, Löscher WN, Wanschitz J, Windpassinger C, Duba HC, Seidl R, Albrecht G, Weirich-Schwaiger H, Zoller H, Utermann G, Auer-Grumbach M, Janecke AR.

Eur J Hum Genet. 2009 Sep;17(9):1154-9. doi: 10.1038/ejhg.2009.29. Epub 2009 Mar 4.

PubMed [citation]

PMID:: 19259128
PMCID:: PMC2986587

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000829220.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 224 of the MPZ protein (p.Asp224Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (CMT) (PMID: 16488608, 19259128, 19882637, 21149811, 27088055). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41024). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MPZ function (PMID: 31173589). 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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