COX11

protein-coding

cytochrome c oxidase copper chaperone COX11, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes a protein which is not a structural subunit, but may be a heme A biosynthetic enzyme involved in COX formation, according to the yeast mutant studies. However, the studies in Rhodobacter sphaeroides suggest that this gene is not required for heme A biosynthesis, but required for stable formation of the Cu(B) and magnesium centers of COX. This human protein is predicted to contain a transmembrane domain localized in the mitochondrial inner membrane. Multiple transcript variants encoding different isoforms have been found for this gene. A related pseudogene has been found on chromosome 6. [provided by RefSeq, Jun 2009]

MANE transcript

NM_004375.5

Inheritance

ClinVar variants

P:4U:34B:5

Top phenotype

Mitochondrial complex IV deficiency, nuclear type 23

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr17:54,951,902-54,968,703

External References & Databases

Ensembl (ENSG00000166260)

Transcript & Mutation Effects

hg38 • Region Span ~16.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COX11* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 26, 2024. The *COX11* gene encodes cytochrome c oxidase assembly factor 11, a mitochondrial respiratory chain complex IV assembly factor. The *COX11* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2022 (PMID: 36030551). *COX11* has been associated with a single disease entity to date; Mitochondrial complex IV deficiency, nuclear type 23 [OMIM#620275]. 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 four unique variants (two missense, two frameshift) identified in three unrelated cases from two publications (PMIDs: 36030551, 38068960). Age of onset ranges from congenital to early infancy. Clinical features in affected individuals are variable and include intrauterine growth restriction, sensorineural hearing loss, poor feeding and failure to thrive, seizures, global developmental delay, and cerebellar and pyramidal signs. Lactate is elevated in cerebrospinal fluid and plasma. Brain imaging showed progressive brain atrophy, dentate nucleus lesions, bilateral basal ganglia hyperintensities, and diffuse white matter disease. 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 August 26, 2024 (SOP Version 10).

mitochondrial complex IV deficiency, nuclear type 23LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859520

Submitter: Ambry Genetics

mitochondrial complex IV deficiency, nuclear type 23LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0859520

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex IV deficiency, nuclear type 23AR

Manifestation: Audiologic/Otolaryngologic; 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

Refs: 36030551; 38068960

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COX11 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 33

Mitochondrial complex IV deficiency, nuclear type 23Total: 8

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004375.5. 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		34 clinvar	3 clinvar		39
nonsense						0
start loss						0
frameshift	2 clinvar					2
splice donor/acceptor (+/-2bp)						0
Total	4	0	34	5	0	43

Highest pathogenic variant AF is 0.0000013690135

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004375.5	RefSeq	NP_004366.1	4	MANE Select
ENST00000299335.8	Ensembl	ENSP00000299335.3	4	MANE Select
NM_001162861.2	RefSeq	NP_001156333.1	4	Standard
NM_001162862.2	RefSeq	NP_001156334.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thermogenesis - Homo sapiens (human)
Oxidative phosphorylation - Homo sapiens (human)
Electron Transport Chain
Copper homeostasis
Gene expression (Transcription)

Biological Process

respiratory gaseous exchange
respiratory chain complex IV assembly
electron transport chain
negative regulation of glucokinase activity
metal ion homeostasis

Molecular Function

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

Cellular Component

mitochondrion
integral component of mitochondrial inner membrane
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000299335
Coding exons: 4
Length: 16884
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125748
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.666	124	147	0.845	0.00000682	1786
Missense (PolyPhen)		40	54.545	0.73334		675
Synonymous	-0.912	63	54.4	1.16	0.00000259	559
Loss of Function	1.99	5	12.7	0.395	6.13e-7	134

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000067	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Exerts its effect at some terminal stage of cytochrome c oxidase synthesis, probably by being involved in the insertion of the copper B into subunit I. {ECO:0000250}.;

Recessive Scores

pRec: 0.170

Intolerance Scores

LoFtool: 0.508
RVIS EVS: 0.01
RVIS percentile EVS: 54.95

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.922

Gene Damage Prediction

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