UQCRQ

protein-coding

ubiquinol-cytochrome c reductase complex III subunit VII, the group of Mitochondrial complex III: ubiquinol-cytochrome c reductase complex subunits

Gene summary

This gene encodes a ubiquinone-binding protein of low molecular mass. This protein is a small core-associated protein and a subunit of ubiquinol-cytochrome c reductase complex III, which is part of the mitochondrial respiratory chain. [provided by RefSeq, Jul 2008]

MANE transcript

NM_014402.5

Inheritance

ClinVar variants

P:1U:24B:16

Top phenotype

Mitochondrial complex III deficiency, nuclear type 4

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr5:132,866,630-132,868,847

External References & Databases

Ensembl (ENSG00000164405)

Transcript & Mutation Effects

hg38 • Region Span ~2.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex III deficiency nuclear type 4LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014065

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex III deficiency nuclear type 4MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014065

Submitter: PanelApp Australia

mitochondrial complex III deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015448

Submitter: Orphanet

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between UQCRQ and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 14, 2019. A single homozygous variant in UQCRQ has been reported in humans with Leigh syndrome spectrum in a single publication in 2008 (PMID: 18439546). The homozygous variant reported in this publication (PMID: 18439546) demonstrated complete penetrance in more than 20 affected individuals in a large consanguineous Israeli Bedouin kindred. Evidence supporting the gene-disease relationship between UQCRQ and Leigh syndrome spectrum includes case-level data of one proband and segregation data from the 2008 study. This gene-disease association is further supported by UQCRQ protein expression in brain. As there is currently only one publication demonstrating UQCRQ’s role in human disease, there is limited evidence to support the relationship between UQCRQ and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 14, 2019 (SOP Version 7).

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *UQCRQ* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 7, 2024. The *UQCRQ* gene encodes ubiquinol-cytochrome *c* reductase (mitochondrial respiratory chain complex III) subunit 7, a small core-associated protein. The first and only report of the *UQCRQ* gene in relation to autosomal recessive primary mitochondrial disease was in 2008 (PMID: 18439546). *UQCRQ* has been associated with one disease entity to date; mitochondrial complex III deficiency, nuclear type 4 [OMIM# 615159]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Of note, *UQCRQ* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on October 14, 2019 (SOP v6), with a final classification of Limited. This current curation for the association with primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous missense variant identified in affected individuals from one kindred in one publication (PMID: 18439546). Affected individuals had LSS, profound global developmental delay, dystonic posturing, athetoid movements, and ataxia. Brain magnetic resonance imaging performed in five affected individuals showed bilateral symmetric abnormal findings in the basal ganglia. Muscle biopsies appeared normal. Plasma lactate ranged from slightly to significantly increased. The mechanism of disease is suspected 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 (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 October 7, 2024 (SOP Version 10).

mitochondrial complex III deficiency nuclear type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014065

Submitter: G2P

Clinical Genomic Database (CGD)

Mitochondrial complex III deficiency, nuclear type 4AR

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

Comments: Individuals may suffer acute episodes of metabolic crisis; Treatment with Mitochondrial cocktail type therapy may be beneficial

Refs: 18439546

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UQCRQ variants in ClinVar

4 Conditions Cataloged

not providedTotal: 29

not specifiedTotal: 21

Mitochondrial complex III deficiency nuclear type 4Total: 8

UQCRQ-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014402.5. 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				13 clinvar		13
missense		1 clinvar	21 clinvar	3 clinvar		25
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	1	24	16	0	41

Highest pathogenic variant AF is 0.0000065621102

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014402.5	RefSeq	NP_055217.2	2	MANE Select
ENST00000378670.8	Ensembl	ENSP00000367939.3	2	MANE Select
ENST00000378665.1	Ensembl	ENSP00000367934.1	2	Standard
ENST00000378665.2	Ensembl	ENSP00000367934.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac muscle contraction - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)

Biological Process

mitochondrial electron transport, ubiquinol to cytochrome c
subthalamus development
pons development
cerebellar Purkinje cell layer development
hippocampus development

Molecular Function

ubiquinol-cytochrome-c reductase activity

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex III

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378670
Coding exons: 2
Length: 1472
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125740
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.416	42	50.3	0.835	0.00000230	534
Missense (PolyPhen)		17	15.737	1.0803		176
Synonymous	-0.429	22	19.6	1.12	9.33e-7	159
Loss of Function	0.632	2	3.22	0.620	1.45e-7	33

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This is a component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is part of the mitochondrial respiratory chain. This subunit, together with cytochrome b, binds to ubiquinone.;
Disease: DISEASE: Mitochondrial complex III deficiency, nuclear 4 (MC3DN4) [MIM:615159]: A disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected. Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance. {ECO:0000269|PubMed:18439546}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0550

Intolerance Scores

LoFtool: 0.371
RVIS EVS: 0.08
RVIS percentile EVS: 59.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

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