CFHR1

protein-coding

complement factor H related 1, the group of Sushi domain containing|Complement system regulators and receptors

Gene summary

This gene encodes a secreted protein belonging to the complement factor H protein family. It binds to Pseudomonas aeruginosa elongation factor Tuf together with plasminogen, which is proteolytically activated. It is proposed that Tuf acts as a virulence factor by acquiring host proteins to the pathogen surface, controlling complement, and facilitating tissue invasion. Mutations in this gene are associated with an increased risk of atypical hemolytic-uremic syndrome. [provided by RefSeq, Oct 2009]

Previous symbols:

HFL1
CFHL1
CFHR1P
HFL2
CFHL1P

MANE transcript

NM_002113.3

Inheritance

AD, AR, Digenic

ClinVar variants

P:2U:58B:24

Top phenotype

Hemolytic-uremic syndrome, atypical, susceptibility to

gnomAD constraint

pLI —, LoF o/e 0.95

Max pathogenic AF

—

Genomic locus

chr1:196,819,731-196,837,159

External References & Databases

Ensembl (ENSG00000244414)

Transcript & Mutation Effects

hg38 • Region Span ~17.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hemolytic uremic syndrome, atypical, susceptibility to, 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009335

Submitter: Ambry Genetics

dense deposit diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019736

Submitter: Orphanet

age related macular degeneration 1LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011285

Submitter: Labcorp Genetics (formerly Invitae)

hemolytic uremic syndrome, atypical, susceptibility to, 1LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0009335

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hemolytic-uremic syndrome, atypical, susceptibility toAD/AR/Digenic

Manifestation: Hematologic; Renal

Intervention: 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)

Comments: Deletions related to hemolytic-uremic syndrome involve a contiguous deletion with CFHR1

Refs: 98489; 17367211; 18006700; 19435718; 20301541

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CFHR1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 58

not providedTotal: 47

Hemolytic uremic syndrome, atypical, susceptibility to, 1Total: 10

Chronic kidney diseaseTotal: 3

Age related macular degeneration 1Total: 2

Cerebral amyloid angiopathy, APP-relatedTotal: 1

Kidney disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002113.3. 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			1 clinvar	10 clinvar	1 clinvar	12
missense		2 clinvar	52 clinvar	9 clinvar		63
nonsense			1 clinvar			1
start loss						0
frameshift			3 clinvar	2 clinvar		5
splice donor/acceptor (+/-2bp)			1 clinvar	2 clinvar		3
Total	0	2	58	23	1	84

Highest pathogenic variant AF is 0.000033463424

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002113.3	RefSeq	NP_002104.2	6	MANE Select
ENST00000320493.10	Ensembl	ENSP00000314299.5	6	MANE Select
NM_001379306.1	RefSeq	NP_001366235.1	6	Standard
NM_001379307.1	RefSeq	NP_001366236.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Innate Immune System
Immune System
Regulation of Complement cascade
Complement cascade

Biological Process

complement activation
regulation of complement activation
negative regulation of protein binding
positive regulation of cytolysis

Molecular Function

protein binding
protein homodimerization activity
protein heterodimerization activity

Cellular Component

extracellular region
extracellular space
protein-containing complex
blood microparticle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320493
Coding exons: 6
Length: 12433
Individuals with no LoFs: 118387
Homozygous LoFs: 138
Heterozygous LoFs: 241
Defined: 118766
p: 0.00160

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.328	184	172	1.07	0.00000890	2104
Missense (PolyPhen)		67	60.487	1.1077		693
Synonymous	-0.751	65	57.7	1.13	0.00000269	624
Loss of Function	0.166	12	12.6	0.950	5.31e-7	181

Population LoF Frequency

Population	CAF	p-value	Status
African	0.028	0.019	notable
Latino/Admixed American	0.0020	0.0017	notable
Ashkenazi Jewish	0.00013	0.00011	rare
East Asian	0.00038	0.00038	rare
Finnish	0.0011	0.00099	notable
European (Non-Finnish)	0.00038	0.00029	rare
South Asian	0.00041	0.00030	rare
Other	0.0012	0.0010	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in complement regulation. The dimerized forms have avidity for tissue-bound complement fragments and efficiently compete with the physiological complement inhibitor CFH. Can associate with lipoproteins and may play a role in lipid metabolism. {ECO:0000269|PubMed:23487775}.;
Disease: 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:17367211}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. A deletion encompassing CFHR1 and CFHR3 is associated with an increased risk of atypical hemolytic uremic syndrome, likely due to a defective regulation of complement activation (PubMed:17367211). Some patients carrying the deletion have serum anti-CFH autoantibodies (PubMed:18006700). {ECO:0000269|PubMed:17367211, ECO:0000269|PubMed:18006700}.;

Intolerance Scores

LoFtool: 0.828
RVIS EVS: 0.77
RVIS percentile EVS: 87.06

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0920

Gene Damage Prediction

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