COA8

protein-coding

cytochrome c oxidase assembly factor 8, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

This gene encodes a protein that localizes to the mitochondria, where it stimulates the release of cytochrome c, thereby promoting programmed cell death. Mutations in this gene have been found in individuals with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

Previous symbols:

C14orf153
APOPT1

MANE transcript

NM_001370595.2

Inheritance

ClinVar variants

P:16U:68B:32

Top phenotype

Mitochondrial complex IV deficiency, nuclear type 17

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr14:103,562,960-103,607,523

External References & Databases

Ensembl (ENSG00000256053)

Transcript & Mutation Effects

hg38 • Region Span ~44.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018576

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COA8* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 11, 2023. This gene was first reported to encode mitochondrial apoptogenic protein 1 (*APOPT1*) however subsequent studies have not shown evidence for a pro-apoptotic role. Rather, this gene is now known to encode cytochrome c oxidase assembly factor 8 (*COA8*) and functions in protecting the nascent COX holoenzyme from oxidative damage, particularly during metal insertion into the enzyme’s catalytic sites (PMID: 31555154). Defects of this protein lead to complex IV deficiency. *COA8* was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 25175347), in several individuals with cavitating leukodystrophy and complex IV deficiency. While various names have been given to the constellation of features seen in those with *COA8*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COA8* 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 (three nonsense, one intronic, two exonic deletions, one missense) identified in eight affected individuals from seven kindreds reported in three publications (PMIDs: 25175347, 29577824, 32637636). Affected individuals have a broad spectrum of features ranging from acute neurometabolic decompensation in late infancy to mild neurologic features in adolescence. Also seen were encephalopathic episodes (acute loss of developmental milestones, somnolence, seizures, pyramidal signs progressing to spastic tetraparesis) that tended to stabilize or improve over time. Age of onset varied from two to five years old, with one adult reported with minimal neurologic features (PMID: 32637636). The outcomes were variable, ranging from death to stabilization/improvement. Muscle biopsies showed complex IV deficiency. Brain imaging showed a cavitating leukodystrophy predominantly involving the posterior cerebral white matter and the corpus callosum in the acute stage after which the abnormalities partially improved and then stabilized in some affected individuals. Metabolic screening labs were not routinely reported. This gene-disease association is also supported by its known biochemical function (PMID: 33340416), model organisms including a drosophila knockdown (PMID: 31555154) and mouse knockout (PMID: 30552096), and functional alteration in human cells (PMIDs: 25175347, 30552096). In summary, there is definitive evidence to support the relationship between *COA8* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 11, 2023 (SOP Version 9).

mitochondrial complex IV deficiency, nuclear type 17DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033652

Submitter: Natera

mitochondrial complex IV deficiency, nuclear type 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033652

Submitter: PanelApp Australia

mitochondrial complex IV deficiency, nuclear type 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033652

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex IV deficiency, nuclear type 17DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033652

Submitter: G2P

Clinical Genomic Database (CGD)

Mitochondrial complex IV deficiency, nuclear type 17AR

Manifestation: Biochemical; 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: 25175347

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COA8 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 119

Inborn genetic diseasesTotal: 33

Mitochondrial complex IV deficiency, nuclear type 17Total: 26

not specifiedTotal: 21

COA8-related disorderTotal: 16

Mitochondrial complex IV deficiency, nuclear type 1Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001370595.2. 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			3 clinvar	24 clinvar		27
missense		2 clinvar	55 clinvar	5 clinvar	3 clinvar	65
nonsense	1 clinvar	2 clinvar				3
start loss			3 clinvar			3
frameshift	4 clinvar	4 clinvar	3 clinvar			11
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	4 clinvar			7
Total	6	10	68	29	3	116

Highest pathogenic variant AF is 0.0042947964

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001370595.2	RefSeq	NP_001357524.1	5	MANE Select
ENST00000409074.8	Ensembl	ENSP00000386485.3	5	MANE Select
NM_001302653.2	RefSeq	NP_001289582.2	5	Standard
NM_001302654.2	RefSeq	NP_001289583.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of smooth muscle cell apoptotic process
positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
positive regulation of release of cytochrome c from mitochondria
intrinsic apoptotic signaling pathway

Cellular Component

mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409074
Coding exons: 5
Length: 44562
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125747
p: 0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.497	114	100	1.14	0.00000465	1321
Missense (PolyPhen)		21	26.964	0.77881		385
Synonymous	-1.16	45	36.1	1.25	0.00000168	350
Loss of Function	1.00	7	10.5	0.666	5.09e-7	131

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the regulation of apoptosis. Mediates mitochondria-induced cell death in vascular smooth muscle cells through the release of cytochrome c from mitochondria, followed by the activation of the caspase cascade. {ECO:0000250|UniProtKB:Q9CQW7}.;

Recessive Scores

pRec: 0.101

Intolerance Scores

RVIS EVS: 0.01
RVIS percentile EVS: 54.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
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