COA6
protein-codingcytochrome c oxidase assembly factor 6, the group of Mitochondrial respiratory chain complex assembly factors
Gene summary
This gene encodes a member of the cytochrome c oxidase subunit 6B family. The encoded protein associates with cytochrome c oxidase may act has an cytochrome c oxidase mitochondrial respiratory complex VI assembly factor. Mutations in this gene may be associated with fatal infantile cardiomyopathy. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]
- C1orf31
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~11.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0014668
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *COA6* and *COA6*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 22, 2024. *COA6* encodes a complex IV assembly factor which participates in the biogenesis of the CuA site for complex IV. The *COA6* gene was first reported in relation to autosomal recessive *COA6*-related primary mitochondrial disease in 2012 (PMID: 22277967). *COA6* has been associated with a single disease entity to date; mitochondrial complex IV deficiency, nuclear type 13 [OMIM#616501]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *COA6*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique variants (one nonsense, two missense) identified in three unrelated cases from three publications (PMIDs: 22277967, 25339201, 35094435). Two of the three reported individuals had fatal infantile cardiomyopathy and lactic acidosis (PMIDs: 22277967, 25339201) and the third had Leigh syndrome and cardiomyopathy (PMID: 35094435). This gene-disease association is further supported by known protein interaction with COX subunits and assembly factors (PMID: 26160915), model systems including *S. cerevisae* (PMIDs: 22984289, 24549041) and *D. rerio* (PMID: 24549041), functional alteration studies in non-patient cells (PMID: 24549041), and rescue studies (PMID: 26160915). Additional publications were reviewed but not included in scoring as a maximum score for experimental evidence had been reached (PMIDs: 31515291, 35750769). In summary, there is definitive evidence to support the relationship between *COA6* and autosomal recessive *COA6*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 22, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0014668
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; 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
Comments: Manifestations include lethal neonatal hypertrophic cardiomyopathy
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COA6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001206641.3. 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 | 12 | 12 | ||||
| missense | 2 | 14 | 1 | 17 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 1 | 3 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 2 | 2 | 16 | 12 | 1 | 33 |
Highest pathogenic variant AF is 0.000008209922
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001193570.2 | 3 | MANE Select | |
| Ensembl | ENSP00000355574.5 | 3 | MANE Select | |
| RefSeq | NP_001013003.1 | 3 | Standard | |
| RefSeq | NP_001288662.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| coa6 | Danio rerio | Structure: post-vent region Quality: decreased length abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Thermogenesis - Homo sapiens (human)
- Metabolism of proteins
- Mitochondrial protein import
Biological Process
- respiratory chain complex IV assembly
- plasma membrane ATP synthesis coupled electron transport
Molecular Function
- RNA binding
- copper ion binding
- protein binding
Cellular Component
- mitochondrion
- mitochondrial intermembrane space
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000366613
- Coding exons
- 3
- Length
- 10594
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125747
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.720 | 50 | 66.5 | 0.752 | 0.00000306 | 810 |
| Missense (PolyPhen) | 16 | 20.088 | 0.79648 | 281 | ||
| Synonymous | -0.0162 | 26 | 25.9 | 1.00 | 0.00000124 | 227 |
| Loss of Function | 0.811 | 4 | 6.18 | 0.648 | 2.61e-7 | 79 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000067 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in the maturation of the mitochondrial respiratory chain complex IV subunit MT-CO2/COX2. Thereby, may regulate early steps of complex IV assembly. Mitochondrial respiratory chain complex IV or cytochrome c oxidase is the component of the respiratory chain that catalyzes the transfer of electrons from intermembrane space cytochrome c to molecular oxygen in the matrix and as a consequence contributes to the proton gradient involved in mitochondrial ATP synthesis. May also be required for efficient formation of respiratory supercomplexes comprised of complexes III and IV. {ECO:0000269|PubMed:24549041, ECO:0000269|PubMed:25959673, ECO:0000269|PubMed:26160915}.;
- Disease
- DISEASE: Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4 (CEMCOX4) [MIM:616501]: An infantile disorder with a fatal course in the first weeks of life, characterized by hypertrophic cardiomyopathy, left ventricular non-compaction, lactic acidosis, metabolic hypotonia, and mitochondrial complex IV deficiency. {ECO:0000269|PubMed:24549041, ECO:0000269|PubMed:25339201, ECO:0000269|PubMed:25959673}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- RVIS EVS
- 0.37
- RVIS percentile EVS
- 74.95
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |