COA5
protein-codingcytochrome c oxidase assembly factor 5, the group of Mitochondrial respiratory chain complex assembly factors
Gene summary
This gene encodes an ortholog of yeast Pet191, which in yeast is a subunit of a large oligomeric complex associated with the mitochondrial inner membrane, and required for the assembly of the cytochrome c oxidase complex. Mutations in this gene are associated with mitochondrial complex IV deficiency, a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to a severe disease affecting several tissues and organs. [provided by RefSeq, Dec 2011]
- C2orf64
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0014667
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *COA5* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 17, 2024. The *COA5* gene encodes cytochrome c oxidase assembly factor 5, a mitochondrial respiratory chain complex IV assembly factor. The first and only report of *COA5* in relation to autosomal recessive primary mitochondrial disease was in 2011 (PMID: 21457908). *COA5* has been associated with a single disease entity to date; mitochondrial complex IV deficiency, nuclear type 9 [OMIM#616500]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous missense variant identified in one case from one publication (PMID: 21457908). This case had hypertrophic cardiomyopathy and died at eight days old. Cultured fibroblasts showed severe complex IV deficiency. Postmortem microscopic investigations showed accumulation of lipid droplets in cardiomyocytes and mitochondrial proliferation. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416). 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/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 17, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0014667
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular
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
Comments: Manifestations include lethal neonatal hypertrophic cardiomyopathy
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COA5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001008215.3. 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 | 7 | 7 | ||||
| missense | 1 | 10 | 1 | 12 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 1 | 0 | 11 | 8 | 0 | 20 |
Highest pathogenic variant AF is 6.8431376e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001008216.1 | 3 | MANE Select | |
| Ensembl | ENSP00000330730.3 | 3 | MANE Select | |
| Ensembl | ENSP00000386934.1 | 3 | Standard | |
| Ensembl | ENSP00000587781.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Thermogenesis - Homo sapiens (human)
Biological Process
- mitochondrial respiratory chain complex IV assembly
Molecular Function
- protein binding
Cellular Component
- mitochondrion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000328709
- Coding exons
- 3
- Length
- 9206
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 125748
- p
- 0.0000596
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.383 | 33 | 39.8 | 0.829 | 0.00000195 | 461 |
| Missense (PolyPhen) | 8 | 13.362 | 0.59872 | 173 | ||
| Synonymous | 0.202 | 16 | 17.1 | 0.938 | 8.97e-7 | 132 |
| Loss of Function | 0.790 | 3 | 4.88 | 0.614 | 2.04e-7 | 64 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00046 | 0.00044 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000055 | 0.000053 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in an early step of the mitochondrial complex IV assembly process. {ECO:0000269|PubMed:21457908}.;
- Disease
- DISEASE: Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 (CEMCOX3) [MIM:616500]: An infantile disorder with a fatal course in the first weeks of life, characterized by hypertrophic cardiomyopathy and mitochondrial complex IV deficiency. Postmortem microscopic investigations show accumulation of lipid droplets in cardiomyocytes and mitochondrial proliferation. {ECO:0000269|PubMed:21457908}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- RVIS EVS
- 0.06
- RVIS percentile EVS
- 58
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.114
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Medium |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |