CFH
protein-codingcomplement factor H, the group of Sushi domain containing|Complement system regulators and receptors
Gene summary
This gene is a member of the Regulator of Complement Activation (RCA) gene cluster and encodes a protein with twenty short consensus repeat (SCR) domains. This protein is secreted into the bloodstream and has an essential role in the regulation of complement activation, restricting this innate defense mechanism to microbial infections. Mutations in this gene have been associated with hemolytic-uremic syndrome (HUS) and chronic hypocomplementemic nephropathy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Oct 2011]
- HF
- HF1
- HF2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~100.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013892
Submitter: ClinGen
CFH was first reported in relation to autosomal recessive C3 glomerulopathy (C3G) in 1997 (Ault et al., PMID: 9312129). C3G is characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment (Smith et al., 2019, PMID: 30692664). The term C3G is inclusive of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance patterns. Therefore, autosomal recessive cases and autosomal dominant cases were reviewed separately. Following review of autosomal dominant C3G, it was determined by expert consensus that heterozygous variation in CFH is a risk factor of C3G, but not associated with Mendelian disease. Eight variants (missense and in-frame indel) that have been reported in 7 probands in 4 publications (PMIDs: 9312129, 14978182, 16612335, 37615951) are included in this curation. Of note, the score of missense variants at cysteine residues have been upgraded to reflect the equivalent score of truncating variants based on their structural impact to factor H, per expert consensus (Ault et al., 1997, PMID: 9312129). The mechanism of pathogenicity is known to be LOF. This gene-disease association is also supported by a mouse and pig model as well as biochemical function (PMIDs: 7883953, 12091909, 16612335). In summary, CFH is definitively associated with autosomal recessive C3G. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Complement-Mediated Kidney Diseases GCEP on the meeting date February 21, 2024 (SOP Version 10.1).
Inheritance Pattern: AD
Disease ID:MONDO:0007471
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012350
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0019736
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007472
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0009335
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012350
Submitter: Ambry Genetics
Inheritance Pattern: Unknown
Disease ID:MONDO:0007472
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0009335
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0016244
Submitter: ClinGen
CFH was first reported in relation to semidominant atypical hemolytic uremic syndrome (aHUS) in 1998 (Warwicker et al., PMID: 9551389). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following diseases have been split into separate entities, aHUS (OMIM: 235400) and C3 glomerulopathy (C3G) (OMIM: 609814). The split curation for semidominant C3G will be conducted separately. Fourteen variants (missense, nonsense, frameshift) that have been reported in eleven probands in three publications (PMIDs: 12424708, 14978182, 28941939) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by experimental evidence (animal models, in vitro functional assays, and biochemical function) (PMIDs: 83964, 16338962, 17517971, 28057640). One mouse model (PMID 17517971 lacking the terminal five SCR cell surface recognition domains of factor H (FHΔ16-20) controlled C3 turnover in plasma but defective control of complement activation on renal endothelium resulted in aHUS. A subsequent mouse (PMID: 28057640) carried a homozygous W1206R missense change in mouse FH that corresponded to the W1183R missense variant in human FH found in multiple aHUS families. This again led to impaired FH activity on cell surface and an aHUS phenotype in the mouse model. Generally, CFH is known to inhibit C3 function (PMID: 83964) and the C-terminal region of CFH is known to be responsible for cell surface binding and complement regulation via glycosaminoglycan and C3b/C3d (PMID: 18684951). Multiple variants in this region of CFH were shown to reduce heparin affinity as well as binding with C3b/C3d (PMID: 16338962) resulting in aHUS. Of note, some variants in CFH can cause aHUS and/or C3G in separate patients, although the mechanism of disease leading to different clinical presentations is not fully understood. In summary, there is definitive evidence supporting the relationship between CFH and semidominant aHUS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over. This classification was approved by the ClinGen Complement Mediated Kidney Diseases GCEP on the meeting date April 19, 2023 (SOP Version 9).
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Ophthalmologic; Renal
Intervention: Allergy/Immunology/Infectious; Hematologic; Pharmacogenomic; Renal
Rationale: In Hemolytic-uremic syndrome, the choice of specific treatment modalities (eg, danazol, plasma exchange, plasma therapy), as well as decision to perform renal transplant, may be dictated by genetic diagnosis, and certain agents/precipitating factors should be avoided (eg, certain medications); In Complement factor H deficiency, antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CFH variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000186.4. 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 | 15 | 204 | 3 | 222 | ||
| missense | 5 | 70 | 791 | 27 | 2 | 895 |
| nonsense | 55 | 27 | 2 | 84 | ||
| start loss | 0 | |||||
| frameshift | 38 | 17 | 3 | 58 | ||
| splice donor/acceptor (+/-2bp) | 21 | 13 | 2 | 1 | 37 | |
| Total | 119 | 127 | 813 | 232 | 5 | 1296 |
Highest pathogenic variant AF is 0.00013693776
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000177.2 | 22 | MANE Select | |
| Ensembl | ENSP00000356399.4 | 22 | MANE Select | |
| RefSeq | NP_001014975.1 | 10 | Standard | |
| Ensembl | ENSP00000352658.2 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Complement and coagulation cascades - Homo sapiens (human)
- Staphylococcus aureus infection - Homo sapiens (human)
- Human Complement System
- Dengue-2 Interactions with Complement and Coagulation Cascades
- Complement and Coagulation Cascades
Biological Process
- complement activation
- complement activation, alternative pathway
- viral process
- regulation of complement activation
Molecular Function
- protein binding
- heparin binding
- heparan sulfate proteoglycan binding
Cellular Component
- extracellular region
- extracellular space
- extracellular exosome
- blood microparticle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000367429
- Coding exons
- 22
- Length
- 95627
- Individuals with no LoFs
- 125728
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 125744
- p
- 0.0000636
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.997 | 588 | 660 | 0.891 | 0.0000335 | 8023 |
| Missense (PolyPhen) | 118 | 208.94 | 0.56477 | 2452 | ||
| Synonymous | -1.76 | 256 | 223 | 1.15 | 0.0000117 | 2220 |
| Loss of Function | 5.89 | 13 | 63.7 | 0.204 | 0.00000290 | 871 |
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 | 0.00011 | 0.00011 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000089 | 0.000088 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Factor H functions as a cofactor in the inactivation of C3b by factor I and also increases the rate of dissociation of the C3bBb complex (C3 convertase) and the (C3b)NBB complex (C5 convertase) in the alternative complement pathway.;
- Disease
- DISEASE: Complement factor H deficiency (CFHD) [MIM:609814]: A disorder that can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure. Laboratory features usually include decreased serum levels of factor H, complement component C3, and a decrease in other terminal complement components, indicating activation of the alternative complement pathway. It is associated with a number of renal diseases with variable clinical presentation and progression, including membranoproliferative glomerulonephritis and atypical hemolytic uremic syndrome. {ECO:0000269|PubMed:10803850, ECO:0000269|PubMed:11158219, ECO:0000269|PubMed:11170895, ECO:0000269|PubMed:11170896, ECO:0000269|PubMed:12020532, ECO:0000269|PubMed:14978182, ECO:0000269|PubMed:16612335, ECO:0000269|PubMed:9312129}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hemolytic uremic syndrome atypical 1 (AHUS1) [MIM:235400]: An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. {ECO:0000269|PubMed:10577907, ECO:0000269|PubMed:10762557, ECO:0000269|PubMed:11851332, ECO:0000269|PubMed:12960213, ECO:0000269|PubMed:14583443, ECO:0000269|PubMed:14978182, ECO:0000269|PubMed:20513133, ECO:0000269|PubMed:9551389}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Other genes may play a role in modifying the phenotype.; DISEASE: Macular degeneration, age-related, 4 (ARMD4) [MIM:610698]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:22019782}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.136
Intolerance Scores
- LoFtool
- 0.358
- RVIS EVS
- 0.52
- RVIS percentile EVS
- 80.37
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.362
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |