COQ2

protein-coding

coenzyme Q2, polyprenyltransferase

Gene summary

This gene encodes an enzyme that functions in the final steps in the biosynthesis of CoQ (ubiquinone), a redox carrier in the mitochondrial respiratory chain and a lipid-soluble antioxidant. This enzyme, which is part of the coenzyme Q10 pathway, catalyzes the prenylation of parahydroxybenzoate with an all-trans polyprenyl group. Mutations in this gene cause coenzyme Q10 deficiency, a mitochondrial encephalomyopathy, and also COQ2 nephropathy, an inherited form of mitochondriopathy with primary renal involvement. [provided by RefSeq, Oct 2009]

MANE transcript

NM_001358921.2

Inheritance

ClinVar variants

P:51U:164B:114

Top phenotype

Coenzyme Q10 deficiency, primary, 1

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr4:83,261,536-83,284,914

External References & Databases

Ensembl (ENSG00000173085)

Transcript & Mutation Effects

hg38 • Region Span ~23.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COQ2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 30, 2023. The *COQ2* gene encodes the 4-hydroxybenzoate polyprenyltransferase protein. This enzyme is required for the synthesis of coenzyme Q10 (CoQ10), which acts as an electron shuttle between enzyme complexes of the mitochondrial respiratory chain. The *COQ2* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2006 (PMID: 16400613). While various names have been given to the constellation of features seen in those with *COQ2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COQ2* phenotype has been lumped into one disease entity according to per the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine variants in eight probands across six publications (PMIDs: 16400613, 17855635, 17332895, 23631824, 15564041, 29637272). Common clinical manifestations include renal involvement (steroid-resistant nephrotic syndrome), hypotonia, cerebral/cerebellar atrophy, encephalopathy and optic atrophy. Age of onset is typically in the first few years of life. 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. Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by known biochemical function, a Drosophila model, and in vitro functional assays in patient cells demonstrating oxidative phosphorylation deficiencies due to variants in COQ2 (PMIDs: 33340416, 27493029, 21703546, 20495179, 26922674). In summary, there is definitive evidence to support the relationship between *COQ2* and autosomal recessive primary mitochondrial disease. More than three years have elapsed since the first assertion of this gene-disease relationship, and no contradictory evidence has emerged. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 30, 2023 (SOP Version 9).

coenzyme Q10 deficiency, primary, 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011829

Submitter: Labcorp Genetics (formerly Invitae)

multiple system atrophyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0007803

Submitter: Genomics England PanelApp

coenzyme Q10 deficiency, primary, 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011829

Submitter: G2P

Clinical Genomic Database (CGD)

Coenzyme Q10 deficiency, primary, 1AR

Manifestation: Biochemical; Musculoskeletal; Neurologic; Renal

Intervention: Biochemical

Rationale: Treatment with coenzyme Q10 has been described as beneficial

Comments: A heterogenous group of disorders has been described, but the molecular etiologies of some are unclear; Variants may contribute to Multiple system atrophy, susceptibility to 1 (AR)

Refs: 16116126; 17855635; 17374725; 17332895; 17420317; 23758206; 24988567; 24988570

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COQ2 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 301

Coenzyme Q10 deficiency, primary, 1Total: 101

Multiple system atrophy 1, susceptibility toTotal: 77

not specifiedTotal: 63

Inborn genetic diseasesTotal: 50

COQ2-related disorderTotal: 41

Coenzyme Q10 deficiencyTotal: 9

Multiple system atrophyTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001358921.2. 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				99 clinvar		99
missense	2 clinvar	13 clinvar	155 clinvar	13 clinvar	2 clinvar	185
nonsense	2 clinvar	7 clinvar	1 clinvar			10
start loss			2 clinvar			2
frameshift	4 clinvar	12 clinvar	4 clinvar			20
splice donor/acceptor (+/-2bp)		11 clinvar	2 clinvar			13
Total	8	43	164	112	2	329

Highest pathogenic variant AF is 0.00018040783

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001358921.2	RefSeq	NP_001345850.1	7	MANE Select
ENST00000647002.2	Ensembl	ENSP00000495761.2	7	MANE Select
NM_015697.9	RefSeq	NP_056512.5	7	Standard
ENST00000311461.7	Ensembl	ENSP00000311835.7	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
coq2	Danio rerio	Structure: yolk Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

coq2

Danio rerio

Structure: yolk

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquinone and other terpenoid-quinone biosynthesis - Homo sapiens (human)
Ubiquinone Biosynthesis
Metabolism of proteins
Metabolism
Ubiquinol biosynthesis

Biological Process

glycerol metabolic process
ubiquinone biosynthetic process
isoprenoid biosynthetic process

Molecular Function

4-hydroxybenzoate decaprenyltransferase activity
transferase activity, transferring alkyl or aryl (other than methyl) groups
4-hydroxybenzoate nonaprenyltransferase activity

Cellular Component

mitochondrion
mitochondrial inner membrane
integral component of mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000311469
Coding exons: 7
Length: 23379
Individuals with no LoFs: 124622
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 124647
p: 0.000100

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0284	194	193	1.01	0.00000936	2592
Missense (PolyPhen)		35	46.649	0.75029		602
Synonymous	-1.21	88	74.7	1.18	0.00000384	887
Loss of Function	1.88	7	14.8	0.472	6.32e-7	199

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000057	0.000056	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.00019	0.00016	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the prenylation of para-hydroxybenzoate (PHB) with an all-trans polyprenyl group. Mediates the second step in the final reaction sequence of coenzyme Q (CoQ) biosynthesis, which is the condensation of the polyisoprenoid side chain with PHB, generating the first membrane-bound Q intermediate. {ECO:0000255|HAMAP-Rule:MF_03189, ECO:0000269|PubMed:15153069, ECO:0000269|PubMed:16400613, ECO:0000269|PubMed:17374725, ECO:0000269|PubMed:27493029}.;
Disease: DISEASE: Multiple system atrophy 1 (MSA1) [MIM:146500]: A progressive neurodegenerative disorder clinically characterized by parkinsonism, cerebellar ataxia, and autonomic, urogenital, and pyramidal dysfunction in various combinations. Pathologically, it is characterized by degeneration of striatonigral and olivopontocerebellar structures, and glial cytoplasmic inclusions that consist of abnormally phosphorylated alpha-synuclein or tau. {ECO:0000269|PubMed:23758206}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.130

Intolerance Scores

LoFtool: 0.523
RVIS EVS: 0.15
RVIS percentile EVS: 64.32

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.330

Gene Damage Prediction

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