NM_000304.4(PMP22):c.199G>C (p.Ala67Pro) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 7, 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:: RCV001047019.4

Allele description [Variation Report for NM_000304.4(PMP22):c.199G>C (p.Ala67Pro)]

NM_000304.4(PMP22):c.199G>C (p.Ala67Pro)

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.199G>C (p.Ala67Pro)

HGVS:

NC_000017.11:g.15239591C>G
NG_007949.1:g.30737G>C
NM_000304.4:c.199G>CMANE SELECT
NM_001281455.2:c.199G>C
NM_001281456.2:c.199G>C
NM_001330143.2:c.199G>C
NM_153321.3:c.199G>C
NM_153322.3:c.199G>C
NP_000295.1:p.Ala67Pro
NP_001268384.1:p.Ala67Pro
NP_001268385.1:p.Ala67Pro
NP_001317072.1:p.Ala67Pro
NP_696996.1:p.Ala67Pro
NP_696997.1:p.Ala67Pro
LRG_263t1:c.199G>C
LRG_263:g.30737G>C
NC_000017.10:g.15142908C>G
NM_000304.2:c.199G>C
NM_000304.3:c.199G>C
NR_104017.2:n.294G>C
NR_104018.2:n.194G>C
Q01453:p.Ala67Pro

Protein change:

A67P; ALA67PRO

Links:

UniProtKB: Q01453#VAR_009661; OMIM: 601097.0010; dbSNP: rs104894623

NCBI 1000 Genomes Browser:

rs104894623

Molecular consequence:

NM_000304.4:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281455.2:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281456.2:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001330143.2:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_153321.3:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_153322.3:c.199G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_104017.2:n.294G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104018.2:n.194G>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
SCV001210949	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 7, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10330345, 11920834, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001210949

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 7, 2023)

germline

clinical testing

PubMed (3)
[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

A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness.

Kovach MJ, Lin JP, Boyadjiev S, Campbell K, Mazzeo L, Herman K, Rimer LA, Frank W, Llewellyn B, Jabs EW, Gelber D, Kimonis VE.

Am J Hum Genet. 1999 Jun;64(6):1580-93.

PubMed [citation]

PMID:: 10330345
PMCID:: PMC1377901

Anticipation in a unique family with Charcot-Marie-Tooth syndrome and deafness: delineation of the clinical features and review of the literature.

Kovach MJ, Campbell KC, Herman K, Waggoner B, Gelber D, Hughes LF, Kimonis VE.

Am J Med Genet. 2002 Apr 1;108(4):295-303. Review.

PubMed [citation]

PMID:: 11920834

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001210949.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 8436). This variant is also known as 248G>C. This missense change has been observed in individuals with Charcot-Marie-Tooth disease and Charcot-Marie-Tooth disease and deafness (PMID: 10330345, 11920834; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 67 of the PMP22 protein (p.Ala67Pro).

#	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 20, 2024

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