NM_000304.4(PMP22):c.215C>T (p.Ser72Leu) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 27, 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:: RCV000456500.8

Allele description [Variation Report for NM_000304.4(PMP22):c.215C>T (p.Ser72Leu)]

NM_000304.4(PMP22):c.215C>T (p.Ser72Leu)

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.215C>T (p.Ser72Leu)

HGVS:

NC_000017.11:g.15239575G>A
NG_007949.1:g.30753C>T
NM_000304.4:c.215C>TMANE SELECT
NM_001281455.2:c.215C>T
NM_001281456.2:c.215C>T
NM_001330143.2:c.215C>T
NM_153321.3:c.215C>T
NM_153322.3:c.215C>T
NP_000295.1:p.Ser72Leu
NP_001268384.1:p.Ser72Leu
NP_001268385.1:p.Ser72Leu
NP_001317072.1:p.Ser72Leu
NP_696996.1:p.Ser72Leu
NP_696997.1:p.Ser72Leu
LRG_263t1:c.215C>T
LRG_263:g.30753C>T
NC_000017.10:g.15142892G>A
NM_000304.2:c.215C>T
NM_000304.3:c.215C>T
NR_104017.2:n.310C>T
NR_104018.2:n.210C>T
Q01453:p.Ser72Leu

Protein change:

S72L; SER72LEU

Links:

UniProtKB: Q01453#VAR_006363; OMIM: 601097.0007; dbSNP: rs104894621

NCBI 1000 Genomes Browser:

rs104894621

Molecular consequence:

NM_000304.4:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281455.2:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281456.2:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330143.2:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_153321.3:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_153322.3:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_104017.2:n.310C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104018.2:n.210C>T - 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
SCV000552821	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8275092, 9004143, 9585367, 10399754, 11314784, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000552821

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 27, 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

Dejerine-Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene.

Roa BB, Dyck PJ, Marks HG, Chance PF, Lupski JR.

Nat Genet. 1993 Nov;5(3):269-73.

PubMed [citation]

PMID:: 8275092

Dejerine-Sottas disease with sensorineural hearing loss, nystagmus, and peripheral facial nerve weakness: de novo dominant point mutation of the PMP22 gene.

Ionasescu VV, Searby C, Greenberg SA.

J Med Genet. 1996 Dec;33(12):1048-9.

PubMed [citation]

PMID:: 9004143
PMCID:: PMC1050822

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000552821.8

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

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 72 of the PMP22 protein (p.Ser72Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dejerine-Sottas disease and congenital hypomyelinating neuropathy (PMID: 8275092, 9004143, 9585367, 10399754, 11314784). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8433). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as 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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