C1QBP
protein-codingcomplement C1q binding protein
Gene summary
The human complement subcomponent C1q associates with C1r and C1s in order to yield the first component of the serum complement system. The protein encoded by this gene is known to bind to the globular heads of C1q molecules and inhibit C1 activation. This protein has also been identified as the p32 subunit of pre-mRNA splicing factor SF2, as well as a hyaluronic acid-binding protein. [provided by RefSeq, Jul 2008]
- HABP1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~16.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0054677
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *C1QBP* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 15, 2022. The *C1QBP* gene encodes complement component C1q-binding protein. This protein is a multifunctional chaperone predicted to have roles in inflammation and infection processes, mitochondrial ribosome biogenesis, regulation of apoptosis, regulation of nuclear transcription, and mitochondrial homeostasis. The *C1QBP* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2017 (PMID: 28942965). While various names have been given to the constellation of features seen in those with *C1QBP*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *C1QBP* 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 10 unique variants (seven missense variants, one in-frame deletion, one frameshift, and one deletion) identified in 11 probands (14 cases total) from seven publications (PMIDs: 28942965, 32652806, 33344382, 33977026, 34419324, 34003581, 35119291). Age of onset in affected individuals varied from in utero to the sixth decade, and outcomes similarly varied from stillbirth/death in first days of life to alive at more than 60 years of age. Features included hypertrophic cardiomyopathy (not seen in all; one case had a successful heart transplant), ophthalmoplegia, ptosis, exercise intolerance, muscle weakness, intrauterine growth restriction, and oligohydramnios. There were no commonalities on imaging. Tissue biopsies identified multiple large scale mtDNA deletions in skeletal muscle and heart; ragged red fibers, ragged blue fibers, and decreased COX histochemical activity in muscle; aggregates of a large number of mitochondria of varying size, altered cristae, parking lot inclusions, unusual triangular crystalline inclusion in muscle; and lipid droplets in liver. Mitochondrial DNA content was increased at 250% of controls in muscle and 600% in liver. Lab values showed lactic acidosis, metabolic acidosis, and elevated CK. Some affected individuals had normal mitochondrial respiratory chain enzyme activities while others had decreased activities of complexes I, III, and IV in muscle and liver. Complex I, IV, V intact steady-state levels were decreased in muscle by BN-PAGE. These levels were normal in some subjects’ cultured fibroblasts and others showed decreased CI and CIV in cultured fibroblasts. The mechanism of disease appears 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, functional alteration in patient cells, and model systems (PMIDs: 35310974, 28498888, 9305894, 22904065, 29123152). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 15, 2022 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0054677
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Neurologic; Renal
Intervention: Cardiovascular
Rationale: Among other features, individuals have been described as manifesting with cardiomyopahty, and awareness may allow early diagnosis and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to C1QBP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001212.4. 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 | 1 | 65 | 1 | 67 | ||
| missense | 3 | 2 | 66 | 6 | 1 | 78 |
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 3 | 1 | 4 | |||
| splice donor/acceptor (+/-2bp) | 3 | 3 | 6 | |||
| Total | 8 | 6 | 70 | 71 | 2 | 157 |
Highest pathogenic variant AF is 0.000018587822
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001203.1 | 6 | MANE Select | |
| Ensembl | ENSP00000225698.4 | 6 | MANE Select | |
| Ensembl | ENSP00000460638.1 | 5 | Standard | |
| Ensembl | ENSP00000460308.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Herpes simplex infection - Homo sapiens (human)
- miR-targeted genes in epithelium - TarBase
- miR-targeted genes in lymphocytes - TarBase
- miR-targeted genes in muscle cell - TarBase
- Human Complement System
Biological Process
- negative regulation of transcription by RNA polymerase II
- mRNA processing
- apoptotic process
- immune response
- complement activation, classical pathway
Molecular Function
- complement component C1q binding
- transcription corepressor activity
- mRNA binding
- protein kinase C binding
- protein binding
Cellular Component
- extracellular space
- nucleus
- nucleolus
- cytoplasm
- mitochondrion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000225698
- Coding exons
- 6
- Length
- 16054
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 125748
- p
- 0.0000636
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.06 | 105 | 140 | 0.748 | 0.00000678 | 1822 |
| Missense (PolyPhen) | 26 | 38.245 | 0.67982 | 483 | ||
| Synonymous | -0.452 | 65 | 60.5 | 1.07 | 0.00000330 | 564 |
| Loss of Function | 0.359 | 11 | 12.4 | 0.890 | 6.09e-7 | 145 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.00010 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Is believed to be a multifunctional and multicompartmental protein involved in inflammation and infection processes, ribosome biogenesis, protein synthesis in mitochondria, regulation of apoptosis, transcriptional regulation and pre-mRNA splicing. At the cell surface is thought to act as an endothelial receptor for plasma proteins of the complement and kallikrein- kinin cascades. Putative receptor for C1q; specifically binds to the globular "heads" of C1q thus inhibiting C1; may perform the receptor function through a complex with C1qR/CD93. In complex with cytokeratin-1/KRT1 is a high affinity receptor for kininogen- 1/HMWK. Can also bind other plasma proteins, such as coagulation factor XII leading to its autoactivation. May function to bind initially fluid kininogen-1 to the cell membrane. The secreted form may enhance both extrinsic and intrinsic coagulation pathways. It is postulated that the cell surface form requires docking with transmembrane proteins for downstream signaling which might be specific for a cell-type or response. By acting as C1q receptor is involved in chemotaxis of immature dendritic cells and neutrophils and is proposed to signal through CD209/DC-SIGN on immature dendritic cells, through integrin alpha-4/beta-1 during trophoblast invasion of the decidua, and through integrin beta-1 during endothelial cell adhesion and spreading. Signaling involved in inhibition of innate immune response is implicating the PI3K- AKT/PKB pathway. Required for protein synthesis in mitochondria (PubMed:28942965). In mitochondrial translation may be involved in formation of functional 55S mitoribosomes; the function seems to involve its RNA-binding activity. May be involved in the nucleolar ribosome maturation process; the function may involve the exchange of FBL for RRP1 in the association with pre-ribosome particles. Involved in regulation of RNA splicing by inhibiting the RNA- binding capacity of SRSF1 and its phosphorylation. Is required for the nuclear translocation of splicing factor U2AF1L4. Involved in regulation of CDKN2A- and HRK-mediated apoptosis. Stabilizes mitochondrial CDKN2A isoform smARF. May be involved in regulation of FOXC1 transcriptional activity and NFY/CCAAT-binding factor complex-mediated transcription. May play a role in antibacterial defense as it can bind to cell surface hyaluronan and inhibit Streptococcus pneumoniae hyaluronate lyase. May be involved in modulation of the immune response; ligation by HCV core protein is resulting in suppression of interleukin-12 production in monocyte- derived dendritic cells. Involved in regulation of antiviral response by inhibiting DDX58- and IFIH1-mediated signaling pathways probably involving its association with MAVS after viral infection. {ECO:0000269|PubMed:10022843, ECO:0000269|PubMed:10479529, ECO:0000269|PubMed:10722602, ECO:0000269|PubMed:11086025, ECO:0000269|PubMed:11859136, ECO:0000269|PubMed:15243141, ECO:0000269|PubMed:16140380, ECO:0000269|PubMed:16177118, ECO:0000269|PubMed:17881511, ECO:0000269|PubMed:18676636, ECO:0000269|PubMed:19004836, ECO:0000269|PubMed:19164550, ECO:0000269|PubMed:20810993, ECO:0000269|PubMed:21536856, ECO:0000269|PubMed:21544310, ECO:0000269|PubMed:22700724, ECO:0000269|PubMed:28942965, ECO:0000269|PubMed:8662673, ECO:0000269|PubMed:8710908, ECO:0000269|PubMed:9461517}.; FUNCTION: (Microbial infection) In infection processes acts as an attachment site for microbial proteins, including Listeria monocytogenes internalin B and Staphylococcus aureus protein A. {ECO:0000269|PubMed:10722602, ECO:0000269|PubMed:10747014}.;
- Disease
- DISEASE: Combined oxidative phosphorylation deficiency 33 (COXPD33) [MIM:617713]: An autosomal recessive disorder caused by multiple mitochondrial respiratory chain defects and impaired mitochondrial energy metabolism. Clinical manifestations are highly variable. Affected infants present with cardiomyopathy accompanied by multisystemic features involving liver, kidney, and brain. Death in infancy is observed in some patients. Children and adults present with myopathy and progressive external ophthalmoplegia. {ECO:0000269|PubMed:28942965}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.957
Intolerance Scores
- LoFtool
- 0.273
- RVIS EVS
- -0.03
- RVIS percentile EVS
- 51.4
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.863
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |