GeneBe

GJB3

protein-coding

gap junction protein beta 3, the group of Gap junction proteins

Gene summary

This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

Previous symbols:
  • DFNA2
  • EKV

MANE transcript

NM_024009.3

Inheritance

AD, AR, Digenic

ClinVar variants

P:13U:143B:55

Top phenotype

Deafness, autosomal recessive; Deafness, autosomal dominant 2B; Deafness digenic

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr1:34,781,214-34,786,369

External References & Databases

Ensembl (ENSG00000188910)NCBI Gene (2707)OMIM (603324)HGNC:4285GenCCUniProt (O75712)AlphaFoldClinVar (GJB3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~5.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuropathy with hearing impairmentSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015351

Submitter: Orphanet

erythrokeratodermia variabilis et progressiva 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033010

Submitter: Labcorp Genetics (formerly Invitae)

erythrokeratodermia variabilis et progressiva 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033010

Submitter: Labcorp Genetics (formerly Invitae)

erythrokeratodermia variabilis et progressiva 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033010

Submitter: G2P

erythrokeratodermia variabilis et progressiva 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033010

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 1ALIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009076

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 1AMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009076

Submitter: G2P

erythrokeratodermia variabilis et progressiva 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033010

Submitter: Genomics England PanelApp

autosomal recessive nonsyndromic hearing loss 1AMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009076

Submitter: G2P

erythrokeratodermia variabilis et progressiva 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033010

Submitter: Genomics England PanelApp

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

erythrokeratodermia variabilis et progressiva 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033010

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

erythrokeratodermia variabilisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017851

Submitter: Orphanet

nonsyndromic genetic hearing lossNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The GJB3 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 3/7/2017. This association was made using case-level data only. Multiple missense and nonsense variants have been reported in humans, however many of these variants are present in high frequency in population databases and/or have no evidence for pathogenicity. 3 variants were considered to have enough evidence to score. GJB3 was first associated with this disease in humans as early as 1998 (Xia et al.). Association is seen in at least 5 probands in 3 publications (12759707, 19744334, 22617145). This gene-disease association is supported by expression studies in rat and mouse cochlea. Of note, this gene has also been implicated in Erythrokeratodermia variabilis. This has been assessed separately. In summary, there is convincing evidence disputing the association between GJB3 and autosomal dominant nonsyndromic hearing loss. More evidence is needed to either support or refute the role GJB3 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/2018.

erythrokeratodermia variabilisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017851

Submitter: ClinGen

The *GJB3* gene was first associated with autosomal dominant erythrokeratodermia variabilis (EKV) in 1998 (Richard et al., PMID: 9843209). At least 12 unique missense variants have been reported in 22 probands in 18 publications (PMIDs: 9843209, 10594760, 10798362, 15948974, 18482034, 21879244, 21188847, 22681493, 23442023, 26632638, 25297803, 21950330, 20497287, 25556823, 31912549, 31793497, 35663771, 35677558). Some variants are reported de novo, however paternity and maternity were not confirmed in most cases. Variants in this gene segregated with disease in 17 additional members in two families (PMIDs: 9843209, 10594760). This gene-disease relationship is also supported by mouse and zebrafish models which have recapitulated partial phenotypes of EKV, and several functional alteration studies (PMIDs: 12176042, 21920315, 22393412, 26251042). Of note, this gene has also been implicated in autosomal dominant nonsyndromic hearing loss which has been assessed separately as Disputed. In summary, there is definitive evidence to support the relationship between *GJB3* and autosomal dominant erythrokeratodermia variabilis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated as Strong by the ClinGen Hearing Loss Working Group on 3/5/2018 as per SOP v6. It was reevaluated on 6/1/2023 as per SOP v9. As a result of this reevaluation, the classification increased from Strong to Definitive due to additional case level evidence from new publications (PMIDs: 31912549, 31793497, 35663771, 35677558).

autosomal dominant nonsyndromic hearing loss 2BLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012976

Submitter: Labcorp Genetics (formerly Invitae)

erythrokeratodermia variabilis et progressiva 1LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033010

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Deafness, autosomal recessive; Deafness, autosomal dominant 2B; Deafness digenicAD/Digenic

Manifestation: Audiologic/Otolaryngologic; Dermatologic; Neurologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Digenic inheritance (with GJB2) has been described

Refs: 1828175; 9843209; 9843210; 10594760; 10798362; 11175305; 12019212; 12452892; 19050930Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GJB3 variants in ClinVar

15 Conditions Cataloged
not providedTotal: 164
Inborn genetic diseasesTotal: 49
Erythrokeratodermia variabilis et progressiva 1Total: 43
GJB3-related disorderTotal: 35
not specifiedTotal: 33
Autosomal dominant nonsyndromic hearing loss 2BTotal: 17
Autosomal recessive nonsyndromic hearing loss 1ATotal: 14
Hearing loss, autosomal recessiveTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024009.3. 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
36
clinvar
2
clinvar
 40
missense
5
clinvar
6
clinvar
124
clinvar
15
clinvar
2
clinvar
 152
nonsense
1
clinvar
1
clinvar
9
clinvar
 11
start loss
1
clinvar
 1
frameshift
7
clinvar
 7
splice donor/acceptor (+/-2bp)
0
Total67143514211

Highest pathogenic variant AF is 0.00024162371

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_024009.3RefSeqNP_076872.11MANE Select
ENST00000373366.3EnsemblENSP00000362464.21MANE Select
NM_001005752.2RefSeqNP_001005752.11Standard
ENST00000373362.3EnsemblENSP00000362460.31Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Calcium Regulation in the Cardiac Cell

Biological Process

  • in utero embryonic development
  • placenta development
  • cell communication
  • spermatogenesis
  • skin development

Molecular Function

  • gap junction channel activity

Cellular Component

  • cytoplasm
  • gap junction
  • connexin complex
  • integral component of membrane
  • cell junction

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000373366
Coding exons
1
Length
5181
Individuals with no LoFs
125690
Homozygous LoFs
0
Heterozygous LoFs
58
Defined
125748
p
0.000231
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.5261871681.110.00001211742
Missense (PolyPhen)9285.2981.0786921
Synonymous0.8856574.70.8700.00000573565
Loss of Function0.95857.910.6324.37e-772

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.00140.0014notable
Finnish00.0absent
European (Non-Finnish)0.000120.00012rare
South Asian0.000360.00036rare
Other0.000160.00016rare

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: Erythrokeratodermia variabilis et progressiva 1 (EKVP1) [MIM:133200]: A form of erythrokeratodermia variabilis et progressiva, a genodermatosis characterized by the coexistence of two independent skin lesions: transient erythema and hyperkeratosis that is usually localized but occasionally occurs in its generalized form. Clinical presentation varies significantly within a family and from one family to another. Palmoplantar keratoderma is present in around 50% of cases. {ECO:0000269|PubMed:10594760, ECO:0000269|PubMed:10798362, ECO:0000269|PubMed:9843209}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 2B (DFNA2B) [MIM:612644]: A form of non-syndromic sensorineural deafness characterized by progressive high frequency hearing loss in adulthood, with milder expression in females. {ECO:0000269|PubMed:9843210}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.164

Intolerance Scores

LoFtool
0.107
RVIS EVS
0.2
RVIS percentile EVS
67.3

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.156

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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