COX5A

protein-coding

cytochrome c oxidase subunit 5A, the group of Mitochondrial complex IV: cytochrome c oxidase subunits

Gene summary

Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit Va of the human mitochondrial respiratory chain enzyme. A pseudogene COX5AP1 has been found in chromosome 14q22. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004255.4

Inheritance

ClinVar variants

P:2U:27B:4

Top phenotype

Mitochondrial complex IV deficiency, nuclear type 20

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr15:74,919,791-74,938,083

External References & Databases

Ensembl (ENSG00000178741)

Transcript & Mutation Effects

hg38 • Region Span ~18.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cytochrome-c oxidase deficiency diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Orphanet

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COX5A* and *COX5A*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 26, 2024. The *COX5A* gene encodes the cytochrome c oxidase (complex IV) subunit 5A. The *COX5A* gene was first reported in relation to autosomal recessive *COX5A*-related primary mitochondrial disease in 2017 (PMID: 28247525). *COX5A* has been associated with a single disease entity to date; mitochondrial complex IV deficiency, nuclear type 20 [OMIM# 619064]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *COX5A*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two homozygous missense variants identified in two unrelated cases from two publications (PMIDs: 28247525, 35246835). The first reported case had early-onset pulmonary arterial hypertension, lactic acidemia, developmental delay, failure to thrive, and isolated complex IV deficiency in skin fibroblasts. Dysmorphic features were also present (frontal bossing, synophrys, deep-set eyes, long eyelashes, short extremities, and short hands and feet). There was a similarly affected sibling. The second case had failure to thrive, short stature, ovarian insufficiency, hypergonadotrophic hypogonadism, metabolic acidosis, cortical atrophy, and complex IV deficiency in skin fibroblasts. 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), mouse model (PMID: 37373547), and zebrafish model (PMID: 17761683). In summary, there is moderate evidence to support the relationship between *COX5A* and autosomal recessive *COX5A*-related primary mitochondrial disease. 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 August 26, 2024 (SOP Version 10).

mitochondrial complex IV deficiency, nuclear type 20LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033655

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex IV deficiency, nuclear type 20LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033655

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Mitochondrial complex IV deficiency, nuclear type 20AR

Manifestation: Biochemical; Cardiovascular; Neurologic

Intervention: General

Rationale: Among other findings, the condition may involve pulmonary artery hypertension, and awareness may allow early management

Refs: 28247525

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COX5A variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 24

not providedTotal: 4

Mitochondrial complex IV deficiency, nuclear type 20Total: 3

COX5A-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004255.4. 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				2 clinvar		2
missense	2 clinvar		23 clinvar	2 clinvar		27
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	2	0	27	4	0	33

Highest pathogenic variant AF is 0.0000013695122

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004255.4	RefSeq	NP_004246.2	4	MANE Select
ENST00000322347.11	Ensembl	ENSP00000317780.6	4	MANE Select
ENST00000562233.5	Ensembl	ENSP00000456253.1	3	Standard
ENST00000562233.6	Ensembl	ENSP00000456253.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cox5aa	Danio rerio	Structure: secondary motor neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

cox5aa

Danio rerio

Structure: secondary motor neuron

Quality: decreased amount

abnormal

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

mitochondrial electron transport, cytochrome c to oxygen
proton transmembrane transport

Molecular Function

cytochrome-c oxidase activity
protein binding
electron transfer activity
metal ion binding

Cellular Component

mitochondrial inner membrane
mitochondrial respiratory chain complex IV

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000322347
Coding exons: 4
Length: 18378
Individuals with no LoFs: 125135
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125136
p: 0.00000400

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.246	65	70.8	0.918	0.00000409	946
Missense (PolyPhen)		23	26.057	0.88267		311
Synonymous	0.0737	23	23.5	0.981	0.00000109	313
Loss of Function	1.89	1	6.00	0.167	2.51e-7	88

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	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This is the heme A-containing chain of cytochrome c oxidase, the terminal oxidase in mitochondrial electron transport.;
Disease: DISEASE: Note=Mitochondrial complex IV deficiency is a rare condition caused by mutation in COX5A that lead to pulmonary arterial hypertension (PAH), failure to thrive and lactic acidemia. {ECO:0000269|PubMed:28247525}.;

Recessive Scores

pRec: 0.288

Intolerance Scores

LoFtool: 0.137
RVIS EVS: -0.16
RVIS percentile EVS: 41.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0872

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium