NM_000304.4(PMP22):c.418T>C (p.Trp140Arg) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 7, 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:: RCV001851451.4

Allele description [Variation Report for NM_000304.4(PMP22):c.418T>C (p.Trp140Arg)]

NM_000304.4(PMP22):c.418T>C (p.Trp140Arg)

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.418T>C (p.Trp140Arg)

HGVS:

NC_000017.11:g.15230982A>G
NG_007949.1:g.39346T>C
NM_000304.4:c.418T>CMANE SELECT
NM_001281455.2:c.418T>C
NM_001281456.2:c.418T>C
NM_153321.3:c.418T>C
NM_153322.3:c.418T>C
NP_000295.1:p.Trp140Arg
NP_001268384.1:p.Trp140Arg
NP_001268385.1:p.Trp140Arg
NP_696996.1:p.Trp140Arg
NP_696997.1:p.Trp140Arg
LRG_263t1:c.418T>C
LRG_263:g.39346T>C
NC_000017.10:g.15134299A>G
NM_000304.2:c.418T>C
NR_104017.2:n.513T>C
NR_104018.2:n.413T>C
p.TRP140ARG

Protein change:

W140R

Links:

dbSNP: rs1555564040

NCBI 1000 Genomes Browser:

rs1555564040

Molecular consequence:

NM_000304.4:c.418T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281455.2:c.418T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281456.2:c.418T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_153321.3:c.418T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_153322.3:c.418T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_104017.2:n.513T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104018.2:n.413T>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002155316	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 7, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11545686, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002155316

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 7, 2022)

germline

clinical testing

PubMed (2)
[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

Screening for mutations in a genetically heterogeneous disorder: DHPLC versus DNA sequence for mutation detection in multiple genes causing Charcot-Marie-Tooth neuropathy.

Takashima H, Boerkoel CF, Lupski JR.

Genet Med. 2001 Sep-Oct;3(5):335-42.

PubMed [citation]

PMID:: 11545686

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002155316.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant disrupts the p.Trp140 amino acid residue in PMP22. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11545686; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt PMP22 protein function. ClinVar contains an entry for this variant (Variation ID: 448091). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 11545686). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 140 of the PMP22 protein (p.Trp140Arg). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Sep 29, 2024

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