UQCC2

protein-coding

ubiquinol-cytochrome c reductase complex assembly factor 2, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

This gene encodes a nucleoid protein localized to the mitochondria inner membrane. The encoded protein affects regulation of insulin secretion, mitochondrial ATP production, and myogenesis through modulation of mitochondrial respiratory chain activity. [provided by RefSeq, Oct 2012]

Previous symbols:

C6orf125
MNF1

MANE transcript

NM_032340.4

Inheritance

ClinVar variants

P:1U:34B:12

Top phenotype

Mitochondrial complex III deficiency, nuclear type 7

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr6:33,694,293-33,711,727

External References & Databases

Ensembl (ENSG00000137288)

Transcript & Mutation Effects

hg38 • Region Span ~17.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex III deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015448

Submitter: Orphanet

mitochondrial complex III deficiency nuclear type 7LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014356

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *UQCC2* and *UQCC2*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 30, 2024. The *UQCC2* gene encodes a complex III assembly factor that cooperates with *UQCC1* to mediate cytochrome b protein expression and subsequent complex III assembly. The *UQCC2* gene was first reported in relation to autosomal recessive *UQCC2*-related primary mitochondrial disease in 2013 (PMID: 24385928). *UQCC2* has been associated with a single disease entity to date; mitochondrial complex III deficiency, nuclear type 7 [OMIM# 615824]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *UQCC2*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two homozygous variants (one splice region variant, one complex missense variant) identified in two unrelated cases from two publications (PMIDs: 24385928, 28804536). The two reported probands had similar presentations including intrauterine growth restriction, neonatal lactic acidosis, and complex III deficiency. One proband was alive at age 9 years and also had renal tubular dysfunction, seizures, global developmental delay, sensorineural hearing loss, and autism spectrum disorder (PMID: 24385928). The other proband died at age 33 days after experiencing respiratory distress and seizures (PMID: 28804536). The mechanism of disease is 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 the relationship between *UQCC2* and autosomal recessive *UQCC2*-related primary mitochondrial disease. However, given the consistent clinical and biochemical phenotype seen in the two reported cases, this Expert Panel elected to upgrade the classification to moderate. 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 September 30, 2024 (SOP Version 10).

mitochondrial complex III deficiency nuclear type 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014356

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mitochondrial complex III deficiency, nuclear type 7AR

Manifestation: Biochemical; Neurologic; Renal

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: 24385928

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UQCC2 variants in ClinVar

3 Conditions Cataloged

not providedTotal: 48

Mitochondrial complex III deficiency nuclear type 7Total: 18

not specifiedTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032340.4. 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			2 clinvar	8 clinvar	1 clinvar	11
missense	1 clinvar		29 clinvar	2 clinvar	1 clinvar	33
nonsense						0
start loss			2 clinvar			2
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	1	0	34	10	2	47

Highest pathogenic variant AF is 0.0000020526127

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032340.4	RefSeq	NP_115716.1	4	MANE Select
ENST00000607484.6	Ensembl	ENSP00000476140.1	4	MANE Select
ENST00000374214.3	Ensembl	ENSP00000363331.3	3	Standard
ENST00000374231.8	Ensembl	ENSP00000363348.4	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of oxidative phosphorylation
mitochondrial respiratory chain complex III assembly
regulation of insulin secretion
positive regulation of mitochondrial translation
positive regulation of cellular protein catabolic process

Molecular Function

protein binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial intermembrane space
mitochondrial matrix
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000607484
Coding exons: 4
Length: 17435
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.499	59	70.8	0.833	0.00000349	811
Missense (PolyPhen)		9	14.192	0.63414		192
Synonymous	0.260	27	28.8	0.938	0.00000151	234
Loss of Function	1.50	4	8.81	0.454	4.58e-7	93

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for the assembly of the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex). Plays a role in the modulation of respiratory chain activities such as oxygen consumption and ATP production and via its modulation of the respiratory chain activity can regulate skeletal muscle differentiation and insulin secretion by pancreatic beta-cells. Involved in cytochrome b translation and/or stability. {ECO:0000269|PubMed:22363741, ECO:0000269|PubMed:24385928}.;

Intolerance Scores

RVIS EVS: 0.06
RVIS percentile EVS: 58.26

Essentials

Essential (CRISPR): E
Essential (gene trap): E

Gene Damage Prediction

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