COX20

protein-coding

cytochrome c oxidase assembly factor COX20, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

This gene encodes a protein that plays a role in the assembly of cytochrome C oxidase, an important component of the respiratory pathway. It contains two transmembrane helices and localizes to the mitochondrial membrane. Mutations in this gene can cause mitochondrial complex IV deficiency, which results in ataxia and muscle hypotonia. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

Previous symbols:

FAM36A

MANE transcript

NM_198076.6

Inheritance

ClinVar variants

P:14U:64B:29

Top phenotype

Mitochondrial complex IV deficiency, nuclear type 11

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr1:244,835,616-244,845,057

External References & Databases

Ensembl (ENSG00000203667)

Transcript & Mutation Effects

hg38 • Region Span ~9.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex IV deficiency, nuclear type 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033645

Submitter: Ambry Genetics

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COX20* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 17, 2022. *COX20* encodes a Cytochrome *c* oxidase (complex IV) assembly factor. *COX20* was first reported in relation to autosomal recessive mitochondrial disease in 2013 (PMID: 23125284). While various names have been given to the constellation of features seen in those with *COX20*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COX20 *phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included seven unique variants, including one nonsense (occurring in the last exon, 4/4), two intronic, and four missense variants, in 16 probands across seven publications from 2013-2021 (PMIDs: 23125284, 30656193, 32606554, 24202787, 31079202, 32999401, 33751098). Of note, the p.Arg14Lys and p.Thr52Pro variants appear to be founder variants, in the Eastern Chinese and Turkish populations, respectively, while the c.157+3G>C and p.Trp74Cys variants appear to be recurrent. *COX20* pathogenic variants were first reported in a child with ataxia, hypotonia, developmental delay, and short stature in the setting of complex IV deficiency in muscle and skin. Subsequent publications have shown expansion of the phenotypic spectrum that ranges from childhood to adolescent onset sensory neuropathy, dystonia, and sensory ataxia, as well as muscle weakness, intellectual disability, and cerebellar atrophy. Loss-of-function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, functional alteration in non-patient cells, rescue in patient cells, and model systems (PMIDs: 22095077, 24403053, 23125284). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 17, 2022 (SOP Version 8).

mitochondrial complex IV deficiency, nuclear type 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033645

Submitter: Labcorp Genetics (formerly Invitae)

cytochrome-c oxidase deficiency diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Orphanet

Clinical Genomic Database (CGD)

Mitochondrial complex IV deficiency, nuclear type 11AR

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

Refs: 23125284; 24202787

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COX20 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 113

Mitochondrial complex IV deficiency, nuclear type 11Total: 48

Inborn genetic diseasesTotal: 20

not specifiedTotal: 12

COX20-related disorderTotal: 8

Mitochondrial complex IV deficiency, nuclear type 1Total: 3

Mitochondrial diseaseTotal: 2

COX20-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198076.6. 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				25 clinvar	1 clinvar	26
missense	3 clinvar	1 clinvar	58 clinvar	2 clinvar	1 clinvar	65
nonsense		3 clinvar	1 clinvar			4
start loss			1 clinvar			1
frameshift		3 clinvar	3 clinvar			6
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	1 clinvar			5
Total	4	10	64	27	2	107

Highest pathogenic variant AF is 0.00087632757

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_198076.6	RefSeq	NP_932342.1	4	MANE Select
ENST00000411948.7	Ensembl	ENSP00000406327.2	4	MANE Select
NM_001312871.1	RefSeq	NP_001299800.1	4	Standard
NM_001312872.1	RefSeq	NP_001299801.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thermogenesis - Homo sapiens (human)
Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription
Respiratory electron transport

Biological Process

aerobic respiration
mitochondrial respiratory chain complex IV assembly

Molecular Function

protein binding

Cellular Component

mitochondrion
mitochondrial inner membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000411948
Coding exons: 4
Length: 9736
Individuals with no LoFs: 125696
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125721
p: 0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.293	51	57.2	0.891	0.00000283	749
Missense (PolyPhen)		20	23.148	0.86401		293
Synonymous	-1.01	25	19.4	1.29	9.24e-7	208
Loss of Function	0.852	3	5.07	0.592	2.10e-7	84

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000033	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000045	0.000044	rare
South Asian	0.00049	0.00049	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Essential for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase (PubMed:23125284). Acts as a chaperone in the early steps of cytochrome c oxidase subunit II (MT-CO2/COX2) maturation, stabilizing the newly synthesized protein and presenting it to metallochaperones SCO1/2 which in turn facilitates the incorporation of the mature MT-CO2/COX2 into the assembling CIV holoenzyme (PubMed:24403053). {ECO:0000269|PubMed:23125284, ECO:0000269|PubMed:24403053}.;
Disease: DISEASE: Mitochondrial complex IV deficiency (MT-C4D) [MIM:220110]: A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients manifest Leigh syndrome. {ECO:0000269|PubMed:23125284, ECO:0000269|PubMed:24202787, ECO:0000269|PubMed:29154948}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: 0.08
RVIS percentile EVS: 59.76

Essentials

Essential (CRISPR): E
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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