NM_000166.6(GJB1):c.266T>C (p.Leu89Pro) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 19, 2017
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:: RCV000552811.7

Allele description [Variation Report for NM_000166.6(GJB1):c.266T>C (p.Leu89Pro)]

NM_000166.6(GJB1):c.266T>C (p.Leu89Pro)

Gene:

GJB1:gap junction protein beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NM_000166.6(GJB1):c.266T>C (p.Leu89Pro)

HGVS:

NC_000023.11:g.71223973T>C
NG_008357.1:g.13762T>C
NM_000166.6:c.266T>CMANE SELECT
NM_001097642.3:c.266T>C
NP_000157.1:p.Leu89Pro
NP_001091111.1:p.Leu89Pro
LRG_245t2:c.266T>C
LRG_245:g.13762T>C
LRG_245p2:p.Leu89Pro
NC_000023.10:g.70443823T>C
NM_000166.5:c.266T>C

Protein change:

L89P

Links:

dbSNP: rs1555937122

NCBI 1000 Genomes Browser:

rs1555937122

Molecular consequence:

NM_000166.6:c.266T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.266T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth Neuropathy X
Identifiers:: MedGen: CN118851

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000658905	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27367520, 26274329, 12457340, 9099841, 17714866, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000658905

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 19, 2017)

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

Aberrant trafficking of a Leu89Pro connexin32 mutant associated with X-linked dominant Charcot-Marie-Tooth disease.

Da Y, Wang W, Liu Z, Chen H, Di L, Previch L, Chen Z.

Neurol Res. 2016 Oct;38(10):897-902. doi: 10.1080/01616412.2016.1204494. Epub 2016 Jul 1.

PubMed [citation]

PMID:: 27367520

Targeted Next-Generation Sequencing for Clinical Diagnosis of 561 Mendelian Diseases.

Liu Y, Wei X, Kong X, Guo X, Sun Y, Man J, Du L, Zhu H, Qu Z, Tian P, Mao B, Yang Y.

PLoS One. 2015;10(8):e0133636. doi: 10.1371/journal.pone.0133636. Erratum in: PLoS One. 2015 Sep 22;10(9):e0139258. doi: 10.1371/journal.pone.0139258. PLoS One. 2016 Jan 28;11(1):e0148154. doi: 10.1371/journal.pone.0148154.

PubMed [citation]

PMID:: 26274329
PMCID:: PMC4537117

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000658905.4

#	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 leucine with proline at codon 89 of the GJB1 protein (p.Leu89Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have found that this missense change impacts the cellular localization of the GJB1-encoded CX32 protein, preventing the formation of functional CX32 gap junctions (PMID: 27367520). This variant has been reported in multiple individuals affected with CMTX1 (PMID: 26274329, 12457340, 9099841) and it has been reported to segregate with disease in a family affected with X-linked dominant Charcot-Marie-Tooth disease (CMTX1) (PMID: 17714866). This variant is also known as leu238pro in the literature.

#	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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