UQCRC2

protein-coding

ubiquinol-cytochrome c reductase core protein 2, the group of M16 metallopeptidases|Mitochondrial complex III: ubiquinol-cytochrome c reductase complex subunits

Gene summary

The protein encoded by this gene is located in the mitochondrion, where it is part of the ubiquinol-cytochrome c reductase complex (also known as complex III). This complex constitutes a part of the mitochondrial respiratory chain. Defects in this gene are a cause of mitochondrial complex III deficiency nuclear type 5. [provided by RefSeq, Jul 2015]

MANE transcript

NM_003366.4

Inheritance

ClinVar variants

P:10U:96B:31

Top phenotype

Mitochondrial complex III deficiency, nuclear type 5

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr16:21,953,288-21,983,660

External References & Databases

Ensembl (ENSG00000140740)

Transcript & Mutation Effects

hg38 • Region Span ~30.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *UQCRC2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 20, 2022. The *UQCRC2* gene encodes a subunit of complex III (UQCRC2) of the mitochondrial respiratory chain. The *UQCRC2* gene was first reported in relation to autosomal recessive mitochondrial disease in 2013 (PMID: 23281071). While various names have been given to the constellation of features seen in those with *UQCRC2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *UQCRC2* 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 two unique homozygous missense variants identified in three cases from three publications (PMIDs: 23281071, 28275242, 33865955). These individuals had neonatal hypoglycemia, lactic acidosis, and hepatopathy; and one individual had bilateral brainstem lesions consistent with Leigh syndrome spectrum. The Mitochondrial Disease Gene Curation Expert Panel reviewed scoring guidance for homozygous variants in cases with consanguinity and decided that no scoring alteration was needed in these three cases given (1) comprehensive analyses (exome sequencing) were performed, (2) homozygous variants are a common cause of mitochondrial disease, and (3) biochemical evidence in these cases supported a complex III defect. Segregation data are available but did not meet criteria to be considered for scoring per ClinGen Gene Curation SOP V8. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by the known biochemical function, functional alteration in patient cells, and rescue in patient cells (PMIDs: 28844695, 23281071, 28275242, 33865955). In summary, there is moderate 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 January 20, 2022 (SOP Version 8).

mitochondrial complex III deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015448

Submitter: Orphanet

mitochondrial complex III deficiency nuclear type 5MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014066

Submitter: Ambry Genetics

mitochondrial complex III deficiency nuclear type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014066

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex III deficiency nuclear type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014066

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mitochondrial complex III deficiency, nuclear type 5AR

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: 23281071; 33865955

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UQCRC2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 113

not specifiedTotal: 66

Mitochondrial complex III deficiency nuclear type 5Total: 15

UQCRC2-related disorderTotal: 7

Mitochondrial diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003366.4. 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				26 clinvar		26
missense	2 clinvar	2 clinvar	87 clinvar	3 clinvar	2 clinvar	96
nonsense			1 clinvar			1
start loss						0
frameshift		3 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)		3 clinvar	7 clinvar			10
Total	2	8	96	29	2	137

Highest pathogenic variant AF is 0.000008675445

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 70 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003366.4	RefSeq	NP_003357.2	14	MANE Select
ENST00000268379.9	Ensembl	ENSP00000268379.4	14	MANE Select
ENST00000561553.5	Ensembl	ENSP00000456232.1	13	Standard
ENST00000561553.6	Ensembl	ENSP00000456232.1	13	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

oxidative phosphorylation
protein processing involved in protein targeting to mitochondrion
aerobic respiration

Molecular Function

endopeptidase activity
protein binding
protein-containing complex binding
metal ion binding

Cellular Component

nucleoplasm
mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex III
mitochondrial respiratory chain complex IV

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000268379
Coding exons: 14
Length: 31001
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 32
Defined: 125746
p: 0.000127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.951	207	249	0.830	0.0000128	2928
Missense (PolyPhen)		27	47.131	0.57287		564
Synonymous	0.639	81	88.7	0.914	0.00000452	911
Loss of Function	2.19	13	24.8	0.524	0.00000123	303

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00044	0.00044	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

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. The core protein 2 is required for the assembly of the complex.;
Disease: DISEASE: Mitochondrial complex III deficiency, nuclear 5 (MC3DN5) [MIM:615160]: 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:23281071}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.281

Intolerance Scores

LoFtool: 0.681
RVIS EVS: 0.22
RVIS percentile EVS: 68.27

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.980

Gene Damage Prediction

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