COQ4

protein-coding

coenzyme Q4

Gene summary

This gene encodes a component of the coenzyme Q biosynthesis pathway. Coenzyme Q, an essential component of the electron transport chain, shuttles electrons between complexes I or II to complex III of the mitochondrial transport chain. This protein appears to play a structural role in stabilizing a complex that contains most of the coenzyme Q biosynthesis enzymes. Mutations in this gene are associated with mitochondrial disorders linked to coenzyme Q deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

MANE transcript

NM_016035.5

Inheritance

ClinVar variants

P:53U:116B:93

Top phenotype

Coenzyme Q10 deficiency 7

gnomAD constraint

pLI —, LoF o/e 1

Max pathogenic AF

—

Genomic locus

chr9:128,322,544-128,334,072

External References & Databases

Ensembl (ENSG00000167113)

Transcript & Mutation Effects

hg38 • Region Span ~11.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014562

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COQ4* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 30, 2023. The *COQ4* gene encodes ubiquinone biosynthesis protein COQ4, which functions as part of the coenzyme Q10 (CoQ10) biosynthetic pathway. The *COQ4* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2015 (PMID: 25658047). While various names have been given to the constellation of features seen in those with *COQ4*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COQ4* 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 eleven unique variants (eight missense, one stop-gained, one frameshift, and one in-frame deletion variant) identified in seven individuals from four publications (PMIDs: 25658047, 30225196, 28540186, 30659264). Affected individuals have a broad spectrum of features that range from an early onset multisystem encephalopathy with myopathy and cardiac involvement to a less severe, later onset ataxia-spasticity disorder. Reduced levels of CoQ10 and reduced activities of complex I+III and II+III are commonly observed in patient tissues and cells. No segregation data were available for scoring. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, and specifically coenzyme Q10 deficiency; early embryonic lethality in a knockout mouse model; wild-type rescue of growth and COQ synthesis defects in a null yeast model; and wild-type rescue of mitochondrial dysfunction in patient-derived iPSCs and differentiated myocytes (PMIDs: 33340416, 18474229, 29539633, 28472853). In summary, there is definitive evidence to support the relationship between *COQ4* and autosomal recessive 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 January 30, 2023 (SOP Version 9).

neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014562

Submitter: G2P

neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014562

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Coenzyme Q10 deficiency 7AR

Manifestation: Biochemical; Cardiovascular; Neurologic

Intervention: Biochemical

Rationale: Treatment with coenzyme Q10 has been described as possibly beneficial

Refs: 22368301; 25658047; 33704555; 33704555; 36047608; 38013626; 38014483

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COQ4 variants in ClinVar

10 Conditions Cataloged

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndromeTotal: 269

not providedTotal: 77

Inborn genetic diseasesTotal: 41

Spastic ataxia 10, autosomal recessiveTotal: 26

not specifiedTotal: 26

COQ4-related disorderTotal: 18

Spastic ataxiaTotal: 4

Developmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016035.5. 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			5 clinvar	84 clinvar		89
missense	8 clinvar	16 clinvar	108 clinvar	7 clinvar	2 clinvar	141
nonsense	3 clinvar	4 clinvar	1 clinvar			8
start loss		2 clinvar	1 clinvar			3
frameshift	7 clinvar	4 clinvar				11
splice donor/acceptor (+/-2bp)	1 clinvar	8 clinvar	1 clinvar			10
Total	19	34	116	91	2	262

Highest pathogenic variant AF is 0.000096488206

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016035.5	RefSeq	NP_057119.3	7	MANE Select
ENST00000300452.8	Ensembl	ENSP00000300452.3	7	MANE Select
NM_001305942.2	RefSeq	NP_001292871.2	3	Standard
ENST00000372875.3	Ensembl	ENSP00000361966.3	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ubiquinone biosynthetic process

Molecular Function

protein binding

Cellular Component

mitochondrion
extrinsic component of mitochondrial inner membrane
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000300452
Coding exons: 7
Length: 11537
Individuals with no LoFs: 125677
Homozygous LoFs: 0
Heterozygous LoFs: 71
Defined: 125748
p: 0.000282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.364	157	170	0.921	0.0000107	1643
Missense (PolyPhen)		73	82.796	0.88168		792
Synonymous	-1.24	87	73.5	1.18	0.00000441	589
Loss of Function	-0.0102	13	13.0	1.00	8.22e-7	124

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00060	rare
Finnish	0.0012	0.0012	notable
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the coenzyme Q biosynthetic pathway. May play a role in organizing a multi-subunit COQ enzyme complex required for coenzyme Q biosynthesis. Required for steady-state levels of other COQ polypeptides. {ECO:0000255|HAMAP- Rule:MF_03111, ECO:0000269|PubMed:18474229}.;

Recessive Scores

pRec: 0.107

Intolerance Scores

RVIS EVS: 0.51
RVIS percentile EVS: 80.01

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.666

Gene Damage Prediction

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