NM_000304.4(PMP22):c.449G>A (p.Gly150Asp) AND Charcot-Marie-Tooth disease, type I

Clinical significance:Pathogenic (Last evaluated: Jul 15, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001209293.1

Allele description [Variation Report for NM_000304.4(PMP22):c.449G>A (p.Gly150Asp)]

NM_000304.4(PMP22):c.449G>A (p.Gly150Asp)

Gene:
PMP22:peripheral myelin protein 22 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p12
Genomic location:
Preferred name:
NM_000304.4(PMP22):c.449G>A (p.Gly150Asp)
HGVS:
  • NC_000017.11:g.15230951C>T
  • NG_007949.1:g.39377G>A
  • NM_000304.4:c.449G>AMANE SELECT
  • NM_001281455.2:c.449G>A
  • NM_001281456.2:c.449G>A
  • NM_153321.3:c.449G>A
  • NM_153322.3:c.449G>A
  • NP_000295.1:p.Gly150Asp
  • NP_001268384.1:p.Gly150Asp
  • NP_001268385.1:p.Gly150Asp
  • NP_696996.1:p.Gly150Asp
  • NP_696997.1:p.Gly150Asp
  • LRG_263t1:c.449G>A
  • LRG_263:g.39377G>A
  • NC_000017.10:g.15134268C>T
  • NM_000304.2:c.449G>A
  • NM_000304.3:c.449G>A
  • NR_104017.2:n.544G>A
  • NR_104018.2:n.444G>A
  • Q01453:p.Gly150Asp
Protein change:
G150D
Links:
UniProtKB: Q01453#VAR_006379; dbSNP: rs879253954
NCBI 1000 Genomes Browser:
rs879253954
Molecular consequence:
  • NM_000304.4:c.449G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281455.2:c.449G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281456.2:c.449G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_153321.3:c.449G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_153322.3:c.449G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_104017.2:n.544G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_104018.2:n.444G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001380720Invitaecriteria provided, single submitter
Pathogenic
(Jul 15, 2019)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Dejerine-Sottas neuropathy in mother and son with same point mutation of PMP22 gene.

Ionasescu VV, Searby CC, Ionasescu R, Chatkupt S, Patel N, Koenigsberger R.

Muscle Nerve. 1997 Jan;20(1):97-9.

PubMed [citation]
PMID:
8995589

Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22.

Schlebach JP, Narayan M, Alford C, Mittendorf KF, Carter BD, Li J, Sanders CR.

J Am Chem Soc. 2015 Jul 15;137(27):8758-68. doi: 10.1021/jacs.5b03743. Epub 2015 Jul 2.

PubMed [citation]
PMID:
26102530
PMCID:
PMC4507940
See all PubMed Citations (11)

Details of each submission

From Invitae, SCV001380720.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This sequence change replaces glycine with aspartic acid at codon 150 of the PMP22 protein (p.Gly150Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to have arisen de novo in an individual affected with Dejerine-Sottas neuropathy (PMID: 8995589). ClinVar contains an entry for this variant (Variation ID: 245805). Multiple experimental studies have shown that this missense change affects the stability of the PMP22 protein and allows for the formation of intracellular protein aggregates instead of normal PMP22 incorporation into the plasma membrane (PMID: 26102530, 18795802, 25385046, 10078969, 15474367, 9425015, 15537650, 10982389). Additionally, this variant has been shown to be responsible for the Trembler mouse phenotype which is used to model Charcot-Marie-Tooth disease in experimental studies (PMID: 1552943). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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