UQCC3
protein-codingubiquinol-cytochrome c reductase complex assembly factor 3, the group of Mitochondrial respiratory chain complex assembly factors
Gene summary
Complex III is a mitochondrial inner membrane protein complex that transfers electrons from ubiquinol to cytochrome c. This gene encodes a protein that functions in complex III assembly. Mutations in this gene result in Mitochondrial complex III deficiency, nuclear type 9. [provided by RefSeq, Dec 2014]
- C11orf83
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014496
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *UQCC3* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 26, 2024. The *UQCC3* gene encodes ubiquinol-cytochrome-c reductase complex assembly factor 3, which is required for the assembly of the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III). The first and only report of *UQCC3* in relation to autosomal recessive primary mitochondrial disease was in 2014 (PMID: 25008109). *UQCC3* has been associated with a single disease entity to date; mitochondrial complex III deficiency, nuclear type 9 [OMIM#616111]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one missense variant identified in the homozygous state in one case from one publication (PMID: 25008109). Clinical features in the single reported case included lactic acidosis, feeding difficulty, hypoglycemia, muscle weakness, developmental delay, and growth delay. 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 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 August 26, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0015448
Submitter: Orphanet
Clinical Genomic Database (CGD)
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to UQCC3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001085372.3. 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 | 6 | 6 | ||||
| missense | 1 | 28 | 5 | 1 | 35 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 1 | 0 | 30 | 11 | 1 | 43 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001078841.1 | 2 | MANE Select | |
| Ensembl | ENSP00000367189.3 | 2 | MANE Select | |
| Ensembl | ENSP00000432692.1 | 2 | Standard | |
| Ensembl | ENSP00000432692.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- mitochondrial electron transport, ubiquinol to cytochrome c
- ATP biosynthetic process
- mitochondrial respiratory chain complex III assembly
- cristae formation
Molecular Function
- phosphatidic acid binding
- cardiolipin binding
Cellular Component
- mitochondrial respiratory chain complex III
- integral component of mitochondrial inner membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000531323
- Coding exons
- 2
- Length
- 3415
- Individuals with no LoFs
- 124694
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 124697
- p
- 0.0000120
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0853 | 53 | 54.8 | 0.968 | 0.00000240 | 577 |
| Missense (PolyPhen) | 9 | 6.147 | 1.4641 | 50 | ||
| Synonymous | 0.428 | 22 | 24.7 | 0.890 | 0.00000112 | 197 |
| Loss of Function | 0.267 | 2 | 2.45 | 0.816 | 1.04e-7 | 29 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000065 | rare |
| 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) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for the assembly of the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex), mediating cytochrome b recruitment and probably stabilization within the complex. Thereby, plays an important role in ATP production by mitochondria. Cardiolipin- binding protein, it may also control the cardiolipin composition of mitochondria membranes and their morphology. {ECO:0000269|PubMed:25008109, ECO:0000269|PubMed:25605331}.;
- Disease
- DISEASE: Mitochondrial complex III deficiency, nuclear 9 (MC3DN9) [MIM:616111]: A form of mitochondrial complex III deficiency, a disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected. MC3DN9 clinical features include feeding difficulties, hypoglycemia, severe lactic acidosis, and delayed psychomotor development. {ECO:0000269|PubMed:25008109}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0805
Intolerance Scores
- RVIS EVS
- 0.61
- RVIS percentile EVS
- 83.07