NM_000304.4(PMP22):c.35A>G (p.His12Arg) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 25, 2019
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:: RCV001036010.5

Allele description [Variation Report for NM_000304.4(PMP22):c.35A>G (p.His12Arg)]

NM_000304.4(PMP22):c.35A>G (p.His12Arg)

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.35A>G (p.His12Arg)

HGVS:

NC_000017.11:g.15260693T>C
NG_007949.1:g.9635A>G
NM_000304.4:c.35A>GMANE SELECT
NM_001281455.2:c.35A>G
NM_001281456.2:c.35A>G
NM_001330143.2:c.35A>G
NM_153321.3:c.35A>G
NM_153322.3:c.35A>G
NP_000295.1:p.His12Arg
NP_001268384.1:p.His12Arg
NP_001268385.1:p.His12Arg
NP_001317072.1:p.His12Arg
NP_696996.1:p.His12Arg
NP_696997.1:p.His12Arg
LRG_263:g.9635A>G
NC_000017.10:g.15164010T>C
NM_000304.3:c.35A>G

Protein change:

H12R

Links:

dbSNP: rs1909248652

NCBI 1000 Genomes Browser:

rs1909248652

Molecular consequence:

NM_000304.4:c.35A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281455.2:c.35A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281456.2:c.35A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330143.2:c.35A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_153321.3:c.35A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_153322.3:c.35A>G - 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
SCV001199353	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 25, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7728152, 26102530, 10078969, 15474367, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001199353

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 25, 2019)

germline

clinical testing

PubMed (5)
[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

Déjérine-Sottas neuropathy is associated with a de novo PMP22 mutation.

Valentijn LJ, Ouvrier RA, van den Bosch NH, Bolhuis PA, Baas F, Nicholson GA.

Hum Mutat. 1995;5(1):76-80.

PubMed [citation]

PMID:: 7728152

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 (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001199353.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant disrupts the p.His12 amino acid residue in PMP22. Other variant(s) that disrupt this residue have been observed in individuals with PMP22-related conditions (PMID: 7728152, 26102530, 10078969, 15474367), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This variant has been reported to affect PMP22 protein function (PMID:¬†10915775). This variant has not been reported in the literature in individuals with PMP22-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 12 of the PMP22 protein (p.His12Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. 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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