GJA5
protein-codinggap junction protein alpha 5, 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 may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013544
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
*GJA5* was first reported in relation to autosomal dominant congenital heart disease in 2004 (Christiansen et al PMID 15117819) when 3 deletions were identified on chromosome 1q21.1 which included *GJA5* as well as several other genes. There have been multiple publications demonstrating deletions and duplications of 1q21.1 in patients with congenital heart disease (PMID 15117819, 19597493, 22318994, 22939634, 24021551, 26279651, 28905115, 35045913). A recurrent missense variant was identified in two patients with tetralogy of Fallot but the maximum allele frequency was above the allele frequency threshold of 1x10-5 so these variants were not scored. This gene disease relationship is supported by expression studies, a mouse model with congenital heart defects, protein interaction data, (PMIDs 9285645, 12842919, 15537493). In summary, the evidence supporting the relationship between *GJA5* and autosomal dominant congenital heart disease has been disputed due to the lack of human genetic evidence and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role GJA5 plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 4/2/2024 (SOP version 10)
Inheritance Pattern: AD
Disease ID:MONDO:0018054
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013544
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013544
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0000992
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: Surveillance (eg, with echocardiography/electrocardiography) and medical/surgical intervention related to arrhythmias and associated sequelae may be beneficial
Comments: For Atrial standstill, digenic inheritance (with SCN5A) has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GJA5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_181703.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 94 | 1 | 96 | ||
| missense | 4 | 189 | 6 | 199 | ||
| nonsense | 1 | 13 | 14 | |||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 16 | 17 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 7 | 0 | 219 | 100 | 1 | 327 |
Highest pathogenic variant AF is 6.8712654e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_859054.1 | 1 | MANE Select | |
| Ensembl | ENSP00000463851.1 | 1 | MANE Select | |
| RefSeq | NP_005257.2 | 1 | Standard | |
| Ensembl | ENSP00000407645.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gja5b | Danio rerio | Structure: iridophore Quality: dispersed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Antiarrhythmic Pathway, Pharmacodynamics
- NOTCH1 regulation of human endothelial cell calcification
- Calcium Regulation in the Cardiac Cell
Biological Process
- skeletal system development
- angiogenesis
- negative regulation of glomerular filtration
- outflow tract morphogenesis
- endothelium development
Molecular Function
- gap junction hemi-channel activity
- connexin binding
- gap junction channel activity involved in SA node cell-atrial cardiac muscle cell electrical coupling
- gap junction channel activity involved in cardiac conduction electrical coupling
- gap junction channel activity involved in atrial cardiac muscle cell-AV node cell electrical coupling
Cellular Component
- integral component of plasma membrane
- gap junction
- connexin complex
- intercalated disc
- cell projection
dbNSFP Gene Annotations
Source:
- 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: Atrial standstill 1 (ATRST1) [MIM:108770]: A rare arrhythmia characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm. {ECO:0000269|PubMed:16790700}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry. A rare GJA5 genotype has been detected in combination with a mutation in SCN5A in a large family with atrial standstill.; DISEASE: Atrial fibrillation, familial, 11 (ATFB11) [MIM:614049]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:20650941}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.175
Intolerance Scores
- LoFtool
- 0.177
- RVIS EVS
- -0.63
- RVIS percentile EVS
- 17.03
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.517
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |