COX8A
protein-codingcytochrome c oxidase subunit 8A, the group of Mitochondrial complex IV: cytochrome c oxidase subunits
Gene summary
The protein encoded by this gene is the terminal enzyme of the respiratory chain, coupling the transfer of electrons from cytochrome c to molecular oxygen, with the concomitant production of a proton electrochemical gradient across the inner mitochondrial membrane. In addition to 3 mitochondrially encoded subunits, which perform the catalytic function, the eukaryotic enzyme contains nuclear-encoded smaller subunits, ranging in number from 4 in some organisms to 10 in mammals. It has been proposed that nuclear-encoded subunits may be involved in the modulation of the catalytic function. This gene encodes one of the nuclear-encoded subunits. [provided by RefSeq, Jul 2008]
- COX8
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~1.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009068
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0009068
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009723
Submitter: ClinGen
The relationship between COX8A and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of June 8, 2020. The COX8A gene encodes cytochrome c oxidase (complex IV) subunit 8A. Defects of this protein lead to complex IV deficiency. The COX8A gene has been reported only once in relation to autosomal recessive Leigh syndrome spectrum, in 2016 (PMID: 26685157), and this has been the only case reported to date. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous variant identified in one case in one publication (PMID: 26685157). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression, and rescue in patient cells (PMIDs: 27977873, 25613900, 26685157). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 8, 2020 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *COX8A* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 18, 2024. The *COX8A* gene encodes cytochrome *c* oxidase (complex IV) subunit 8A. Defects of this protein lead to complex IV deficiency. The first and only case report of *COX8A*-related autosomal recessive primary mitochondrial disease was in 2016 (PMID: 26685157), in an individual from a consanguineous family with Leigh syndrome spectrum (LSS) disorder, congenital scoliosis, developmental delay, pulmonary hypertension, epilepsy, and lactic acidosis. While various names have been given to the constellation of features seen in those with *COX8A*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the COX8A phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *COX8A* was first curated by this Expert Panel for its association with LSS on June 8, 2020 (SOP V7), with a final classification of Limited. This current curation for the association with primary mitochondrial disease includes the single case included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This included one intronic variant impacting splicing (PMID: 26685157) in the single reported proband. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of COX8A as a subunit of complex IV, as well as functional alteration in non-patient cells (PMID: 33705280) and rescue in patient cells (PMID: 26685157). In summary, there is limited evidence to support this gene-disease relationship given that only one case has been reported to date. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 18, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: LiferaOmics
ClinGen: AR mitochondrial disease (complex IV deficiency) Classification: Limitted, approved 2024 based on PMID 26685157 Genetic evidence – Published: PMID: 26685157 reports 1 proband with a homozygous splice-site COX8A variant causing aberrant splicing and isolated complex IV deficiency resembling Leigh-like syndrome and epilepsy; case-level (biallelic predicted null, consanguinity not reported) = 2.0; segregation = 0; case-control = 0. Published genetic evidence total = 2.0/12 Genetic evidence – our case: 1 proband, positive consanguinity, no other affected siblings; homozygous frameshift NM_004074.2:c.111del;p.(Met38TrpfsTer12) (predicted loss-of-function). Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity deduction applied) = 1.0; segregation = 0; case-control = 0. our case contribution = 1.0/12 Total genetic evidence (published + our case) = 3.0/12 Experimental evidence – Published:PMID: 26685157 COX8A encodes a structural subunit of mitochondrial complex IV; functional studies including patient fibroblast rescue (lentiviral expression of wild-type COX8A) demonstrate rescue of complex IV activity, supporting gene disease mechanism. Experimental evidence total = 2.5/6 Overall score = 5.5
Inheritance Pattern: AR
Disease ID:MONDO:0033650
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Musculoskeletal; 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COX8A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004074.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 8 | 1 | 9 | |||
| missense | 14 | 2 | 16 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 1 | 0 | 15 | 10 | 1 | 27 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004065.1 | 2 | MANE Select | |
| Ensembl | ENSP00000321260.3 | 2 | MANE Select | |
| Ensembl | ENSP00000772015.1 | 2 | Standard | |
| Ensembl | ENSP00000806755.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cardiac muscle contraction - Homo sapiens (human)
- Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
- Alzheimer,s disease - Homo sapiens (human)
- Huntington,s disease - Homo sapiens (human)
- Thermogenesis - Homo sapiens (human)
Biological Process
- generation of precursor metabolites and energy
- electron transport chain
- proton transmembrane transport
Molecular Function
- cytochrome-c oxidase activity
- protein binding
Cellular Component
- mitochondrion
- mitochondrial inner membrane
- integral component of membrane
- respiratory chain complex IV
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000314133
- Coding exons
- 2
- Length
- 1937
- Individuals with no LoFs
- 117625
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 117626
- p
- 0.00000425
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.154 | 35 | 37.7 | 0.929 | 0.00000194 | 412 |
| Missense (PolyPhen) | 9 | 11.364 | 0.79198 | 104 | ||
| Synonymous | 0.859 | 15 | 19.9 | 0.755 | 0.00000109 | 166 |
| Loss of Function | 0.368 | 1 | 1.48 | 0.674 | 6.21e-8 | 22 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000030 | 0.000030 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: This protein is one of the nuclear-coded polypeptide chains of cytochrome c oxidase, the terminal oxidase in mitochondrial electron transport.;
Recessive Scores
- pRec
- 0.127
Intolerance Scores
- RVIS EVS
- 0.26
- RVIS percentile EVS
- 69.83
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.429
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |