GeneBe

GJB1

protein-coding

gap junction protein beta 1, the group of Gap junction proteins

Gene summary

This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]

Previous symbols:
  • CMTX1
  • CMTX

MANE transcript

NM_000166.6

Inheritance

XL

ClinVar variants

P:308U:382B:119

Top phenotype

Charcot-Marie-Tooth neuropathy, X-linked dominant, 1

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:71,212,811-71,225,516

External References & Databases

Ensembl (ENSG00000169562)NCBI Gene (2705)OMIM (304040)HGNC:4283GenCCUniProt (P08034)AlphaFoldClinVar (GJB1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~12.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease X-linked dominant 1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010549

Submitter: Labcorp Genetics (formerly Invitae)

X-linked progressive cerebellar ataxiaSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010547

Submitter: Orphanet

Charcot-Marie-Tooth disease X-linked dominant 1SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010549

Submitter: Orphanet

Charcot-Marie-Tooth disease X-linked dominant 1DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010549

Submitter: ClinGen

GJB1 was first reported in relation to Charcot Marie Tooth (CMT) disease in 1993 (Bergoffen et al., 1993; PMID: 8266101) At least 450 unique variants, including missense, nonsense, frameshift, and indels have been reported in humans (reviewed in Bortolozzi, 2018; PMID: 30042657; Kleopa et al., 2012; PMID: 22771394). There are a variant databases describing GJB1 variants of interest in CMT, and include (1) the Inherited Neuropathy Variant Database (greater than 700 GJB1 variants; URL: http://hihg.med.miami.edu/code/http/cmt/public_html/index.html#/), and (2) the GJB1 Gene homepage on LOVD (URL: https://databases.lovd.nl/shared/genes/GJB1). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This gene-disease relationship has been studied for over 20 years, therefore a significant amount of case-level data and segregation is available, however the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by expression studies and animal models. GJB1 has 2 exons of which the entirety of the protein coding region is encoded by exon 2, therefore nonsense variants are not predicted to undergo nonsense mediated decay. The molecular mechanism associated with CMT is loss of functional gap junction function, including destabilization or loss of hetero- and homo-dimerization with connexins, and perturbation of ion and small molecule exchange across the multilamellar layers of myelin sheath (reviewed in Scherer and Wrabetz, 2008; PMID: 18803325; Nualart-Marti et al., 2013; PMID: 22326946). In summary, GJB1 is DEFINITIVELY associated with x-linked Charcot Marie Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Charcot Marie Tooth Gene Curation Expert Panel on Jan 14, 2020.

Charcot-Marie-Tooth disease X-linked dominant 1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010549

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease X-linked dominant 1DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010549

Submitter: Natera

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth neuropathy, X-linked dominant, 1XL

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 8266101; 10487913; 17100997; 17353473; 21254193; 21504505; 21692908; 21922480; 21692908; 22483671; 22577229Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GJB1 variants in ClinVar

27 Conditions Cataloged
Charcot-Marie-Tooth Neuropathy XTotal: 503
Charcot-Marie-Tooth diseaseTotal: 383
Charcot-Marie-Tooth disease X-linked dominant 1Total: 235
not providedTotal: 185
Inborn genetic diseasesTotal: 56
GJB1-related disorderTotal: 53
not specifiedTotal: 43
Peripheral neuropathyTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000166.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
3
clinvar
104
clinvar
4
clinvar
 113
missense
59
clinvar
147
clinvar
329
clinvar
9
clinvar
2
clinvar
 546
nonsense
25
clinvar
6
clinvar
7
clinvar
 38
start loss
4
clinvar
1
clinvar
3
clinvar
 8
frameshift
40
clinvar
20
clinvar
36
clinvar
 96
splice donor/acceptor (+/-2bp)
1
clinvar
3
clinvar
4
clinvar
 8
Total1311773821136809

Highest pathogenic variant AF is 0.000009018921

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000166.6RefSeqNP_000157.11MANE Select
ENST00000361726.7EnsemblENSP00000354900.61MANE Select
NM_001097642.3RefSeqNP_001091111.11Standard
NM_001440770.1RefSeqNP_001427699.11Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neural Crest Differentiation
  • Common Pathways Underlying Drug Addiction
  • Calcium Regulation in the Cardiac Cell
  • Vesicle-mediated transport
  • Membrane Trafficking

Biological Process

  • cell-cell signaling
  • nervous system development
  • purine ribonucleotide transport
  • gap junction assembly
  • protein complex oligomerization

Molecular Function

  • gap junction channel activity
  • protein homodimerization activity

Cellular Component

  • endoplasmic reticulum membrane
  • connexin complex
  • integral component of membrane
  • lateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000374022
Coding exons
1
Length
10323
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.03661310.5020.00001171828
Missense (PolyPhen)1054.8090.18245839
Synonymous0.4134952.80.9280.00000445604
Loss of Function2.3006.150.005.38e-782

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.;
Disease
DISEASE: Charcot-Marie-Tooth disease, X-linked dominant, 1 (CMTX1) [MIM:302800]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies characterized by severely reduced motor nerve conduction velocities (NCVs) (less than 38m/s) and segmental demyelination and remyelination, and primary peripheral axonal neuropathies characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy. CMTX1 has both demyelinating and axonal features. Central nervous system involvement may occur. {ECO:0000269|PubMed:10071100, ECO:0000269|PubMed:10220155, ECO:0000269|PubMed:10234007, ECO:0000269|PubMed:10586284, ECO:0000269|PubMed:10732813, ECO:0000269|PubMed:10737979, ECO:0000269|PubMed:10873293, ECO:0000269|PubMed:10894999, ECO:0000269|PubMed:10923043, ECO:0000269|PubMed:10938190, ECO:0000269|PubMed:11030070, ECO:0000269|PubMed:11140841, ECO:0000269|PubMed:11180613, ECO:0000269|PubMed:11437164, ECO:0000269|PubMed:11438991, ECO:0000269|PubMed:11562788, ECO:0000269|PubMed:11571214, ECO:0000269|PubMed:11723288, ECO:0000269|PubMed:11835375, ECO:0000269|PubMed:11891346, ECO:0000269|PubMed:12185164, ECO:0000269|PubMed:12207932, ECO:0000269|PubMed:12325071, ECO:0000269|PubMed:12402337, ECO:0000269|PubMed:12477701, ECO:0000269|PubMed:12497641, ECO:0000269|PubMed:12536289, ECO:0000269|PubMed:12707076, ECO:0000269|PubMed:14627639, ECO:0000269|PubMed:15241803, ECO:0000269|PubMed:15468313, ECO:0000269|PubMed:15852376, ECO:0000269|PubMed:27234031, ECO:0000269|PubMed:7477983, ECO:0000269|PubMed:7833935, ECO:0000269|PubMed:8004109, ECO:0000269|PubMed:8162049, ECO:0000269|PubMed:8266101, ECO:0000269|PubMed:8628473, ECO:0000269|PubMed:8698335, ECO:0000269|PubMed:8733054, ECO:0000269|PubMed:8737658, ECO:0000269|PubMed:8807343, ECO:0000269|PubMed:8829637, ECO:0000269|PubMed:8889588, ECO:0000269|PubMed:8956046, ECO:0000269|PubMed:8990008, ECO:0000269|PubMed:9018031, ECO:0000269|PubMed:9099841, ECO:0000269|PubMed:9187667, ECO:0000269|PubMed:9272161, ECO:0000269|PubMed:9361298, ECO:0000269|PubMed:9452025, ECO:0000269|PubMed:9452099, ECO:0000269|PubMed:9469569, ECO:0000269|PubMed:9633821, ECO:0000269|PubMed:9818870, ECO:0000269|PubMed:9856562, ECO:0000269|Ref.12}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dejerine-Sottas syndrome (DSS) [MIM:145900]: A severe degenerating neuropathy of the demyelinating Charcot-Marie-Tooth disease category, with onset by age 2 years. Characterized by motor and sensory neuropathy with very slow nerve conduction velocities, increased cerebrospinal fluid protein concentrations, hypertrophic nerve changes, delayed age of walking as well as areflexia. There are both autosomal dominant and autosomal recessive forms of Dejerine-Sottas syndrome. {ECO:0000269|PubMed:15947997}. Note=The gene represented in this entry may act as a disease modifier.;

Recessive Scores

pRec
0.440

Intolerance Scores

RVIS EVS
0.21
RVIS percentile EVS
67.72

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.801

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.