NM_000304.4(PMP22):c.420G>A (p.Trp140Ter) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 4, 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:: RCV000803362.3

Allele description [Variation Report for NM_000304.4(PMP22):c.420G>A (p.Trp140Ter)]

NM_000304.4(PMP22):c.420G>A (p.Trp140Ter)

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.420G>A (p.Trp140Ter)

HGVS:

NC_000017.11:g.15230980C>T
NG_007949.1:g.39348G>A
NM_000304.4:c.420G>AMANE SELECT
NM_001281455.2:c.420G>A
NM_001281456.2:c.420G>A
NM_153321.3:c.420G>A
NM_153322.3:c.420G>A
NP_000295.1:p.Trp140Ter
NP_001268384.1:p.Trp140Ter
NP_001268385.1:p.Trp140Ter
NP_696996.1:p.Trp140Ter
NP_696997.1:p.Trp140Ter
LRG_263:g.39348G>A
NC_000017.10:g.15134297C>T
NM_000304.3:c.420G>A
NR_104017.2:n.515G>A
NR_104018.2:n.415G>A

Protein change:

W140*

Links:

dbSNP: rs1597597527

NCBI 1000 Genomes Browser:

rs1597597527

Molecular consequence:

NR_104017.2:n.515G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104018.2:n.415G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000304.4:c.420G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001281455.2:c.420G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001281456.2:c.420G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_153321.3:c.420G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_153322.3:c.420G>A - nonsense - [Sequence Ontology: SO:0001587]

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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membrane protein [Mycobacterium phage LittleB]
membrane protein [Mycobacterium phage LittleB]
gi|1102333136|gb|APC44146.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000943228	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 4, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21149811, 21252112, 23965407, 22006697, 32376792, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000943228

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 4, 2023)

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

Analyzing histopathological features of rare charcot-marie-tooth neuropathies to unravel their pathogenesis.

Benedetti S, Previtali SC, Coviello S, Scarlato M, Cerri F, Di Pierri E, Piantoni L, Spiga I, Fazio R, Riva N, Natali Sora MG, Dacci P, Malaguti MC, Munerati E, Grimaldi LM, Marrosu MG, De Pellegrin M, Ferrari M, Comi G, Quattrini A, Bolino A.

Arch Neurol. 2010 Dec;67(12):1498-505. doi: 10.1001/archneurol.2010.303.

PubMed [citation]

PMID:: 21149811

Inherited demyelinating neuropathies with micromutations of peripheral myelin protein 22 gene.

Taioli F, Cabrini I, Cavallaro T, Acler M, Fabrizi GM.

Brain. 2011 Feb;134(Pt 2):608-17. doi: 10.1093/brain/awq374. Epub 2011 Jan 19.

PubMed [citation]

PMID:: 21252112

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000943228.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PMP22 protein in which other variant(s) (p.Leu145Argfs*10) have been determined to be pathogenic (PMID: 21149811, 21252112, 23965407). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 648604). This premature translational stop signal has been observed in individual(s) with clinical features of PMP22-related conditions (PMID: 22006697, 32376792). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp140*) in the PMP22 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the PMP22 protein.

#	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 28, 2024

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