SERPING1

protein-coding

serpin family G member 1, the group of Serpin peptidase inhibitors|Complement system regulators and receptors

Gene summary

This gene encodes a highly glycosylated plasma protein involved in the regulation of the complement cascade. Its encoded protein, C1 inhibitor, inhibits activated C1r and C1s of the first complement component and thus regulates complement activation. It is synthesized in the liver, and its deficiency is associated with hereditary angioneurotic oedema (HANE). Alternative splicing results in multiple transcript variants encoding the same isoform. [provided by RefSeq, May 2020]

Previous symbols:

C1NH

MANE transcript

NM_000062.3

Inheritance

AD, SD, AR

ClinVar variants

P:379U:223B:151

Top phenotype

Angioedema, hereditary, 1

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr11:57,597,387-57,619,171

External References & Databases

Ensembl (ENSG00000149131)

Transcript & Mutation Effects

hg38 • Region Span ~21.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary angioedema with C1Inh deficiencyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0033946

Submitter: ClinGen

The relationship between *SERPING1* and hereditary angioedema with C1Inh deficiency (HAE-C1-INH), an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of May, 2022. *SERPING1* encodes C1 esterase inhibitor (C1-INH), involved in the regulation of the complement cascade by inhibiting activated C1r and C1s of the first complement component. Hereditary angioedema is characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. The majority of HAE cases has a *SERPING1* variant as the underlying cause, which results in C1-INH deficiency. Two variants of C1-INH-HAE are described: C1-INH type I results from a failure to synthesize C1-INH, whereas in type II, an abnormal, non-functional protein is synthesized (PMID: 34065094). *SERPING1* was first reported in relation to autosomal dominant HAE-C1-INH as early as 1989 by Ariga et al (PMID: 2723063). More than a 100 nonsense, splice site, frameshift, deletion/duplication and missense variants have been reported in humans in the ClinVar database. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 13 probands in 7 publications (PMID: 2723063, 3587308, 35386643, 31982983, 2118657, 12402344, 7883978). Variants segregated with disease in several additional family members (PMID: 3587308, 31982983). The mechanism for disease is haploinsufficiency (HAE-C1-INH type I) and dominant negative (HAE-C1-INH type II). Summary of experimental data (6 points): This gene-disease association is supported by in vitro functional assays and animal models. C1-INH plays a central role in the kallikrein-kinin system. C1-INH has a crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins (PMID: 35958943, 9234243). SERPING1 performs a role similar to PLG and F12, which are also involved in the coagulation and complement activation pathways (PMID: 9234243, 33535668). Serping1 -/- mouse has been recently described, which recapitulates the acute angioedema phenotype (PMID: 34354123). Heterozygous C1 esterase inhibitor deficient mice showed significantly lower serum levels of murine C1-INH and increased vascular permeability, which were restored to wild-type levels when AAV-mediated human C1-INH was introduced to heterozygous mice (PMID: 30059156). In summary, *SERPING*1 is definitively associated with autosomal dominant hereditary angioedema with C1Inh deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

hereditary angioedema type 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015053

Submitter: Orphanet

hereditary angioedema type 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015054

Submitter: Orphanet

hereditary angioedema with C1Inh deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033946

Submitter: Labcorp Genetics (formerly Invitae)

hereditary angioedema with C1Inh deficiencySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0033946

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Angioedema, hereditary, 1AD/AR

Manifestation: Allergy/Immunology/Infectious; Gastrointestinal

Intervention: Allergy/Immunology/Infectious

Rationale: Medical treatment (eg, with C1 inhibitor concentrate, ecallantide, icatabant) may be beneficial to prevent and/or treat acute attacks

Refs: 4393526; 4551861; 792688; 7091182; 3587308; 3653633; 3056508; 3693762; 2723063; 2365061; 2296585; 1885769; 1684567; 1339401; 1459574; 8396558; 8330878; 7618673; 7883978; 8755917; 8628358; 11700154; 11743247; 15971231; 16470590; 16813612 ; 17137866; 17502473; 19752569; 20695852; 20818887; 20818888; 20818886; 21208117; 21864911; 22748405; 22800873; 22831796; 22882460; 23123409; 23437219; 23583915; 23607500; 23678554; 23689237

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SERPING1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 530

Hereditary angioedema type 1Total: 294

Inborn genetic diseasesTotal: 75

SERPING1-related disorderTotal: 51

not specifiedTotal: 42

Hereditary angioedema with C1Inh deficiencyTotal: 35

AngioedemaTotal: 14

C1 inhibitor deficiencyTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000062.3. 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			5 clinvar	111 clinvar	2 clinvar	118
missense	49 clinvar	72 clinvar	216 clinvar	35 clinvar	2 clinvar	374
nonsense	50 clinvar	2 clinvar				52
start loss	5 clinvar					5
frameshift	135 clinvar	26 clinvar	1 clinvar	1 clinvar		163
splice donor/acceptor (+/-2bp)	33 clinvar	7 clinvar	1 clinvar			41
Total	272	107	223	147	4	753

Highest pathogenic variant AF is 0.0000065719432

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 94 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000062.3	RefSeq	NP_000053.2	7	MANE Select
ENST00000278407.9	Ensembl	ENSP00000278407.4	7	MANE Select
NM_001032295.2	RefSeq	NP_001027466.1	7	Standard
ENST00000340687.10	Ensembl	ENSP00000341861.6	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Complement and coagulation cascades - Homo sapiens (human)
Pertussis - Homo sapiens (human)
Human Complement System
Dengue-2 Interactions with Complement and Coagulation Cascades
Complement and Coagulation Cascades

Biological Process

negative regulation of complement activation, lectin pathway
platelet degranulation
complement activation, classical pathway
aging
blood coagulation, intrinsic pathway

Molecular Function

serine-type endopeptidase inhibitor activity
protein binding

Cellular Component

extracellular region
extracellular space
platelet alpha granule lumen
collagen-containing extracellular matrix
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000278407
Coding exons: 7
Length: 17467
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125734
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.06	213	261	0.815	0.0000143	3275
Missense (PolyPhen)		31	75.798	0.40898		1010
Synonymous	-0.190	111	108	1.02	0.00000608	1040
Loss of Function	3.31	1	14.7	0.0680	6.54e-7	195

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Activation of the C1 complex is under control of the C1- inhibitor. It forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein. {ECO:0000269|PubMed:8495195}.;
Disease: DISEASE: Hereditary angioedema (HAE) [MIM:106100]: An autosomal dominant disorder characterized by episodic local swelling involving subcutaneous or submucous tissue of the upper respiratory and gastrointestinal tracts, face, extremities, and genitalia. Hereditary angioedema due to C1 esterase inhibitor deficiency is comprised of two clinically indistinguishable forms. In hereditary angioedema type 1, serum levels of C1 esterase inhibitor are decreased, while in type 2, the levels are normal or elevated, but the protein is non-functional. {ECO:0000269|PubMed:12773530, ECO:0000269|PubMed:1363816, ECO:0000269|PubMed:1451784, ECO:0000269|PubMed:14635117, ECO:0000269|PubMed:16409206, ECO:0000269|PubMed:2118657, ECO:0000269|PubMed:2296585, ECO:0000269|PubMed:22994404, ECO:0000269|PubMed:2365061, ECO:0000269|PubMed:24456027, ECO:0000269|PubMed:3178731, ECO:0000269|PubMed:7814636, ECO:0000269|PubMed:7883978, ECO:0000269|PubMed:8172583, ECO:0000269|PubMed:8529136, ECO:0000269|PubMed:8755917, ECO:0000269|Ref.41}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.215

Intolerance Scores

LoFtool: 0.00565
RVIS EVS: -0.65
RVIS percentile EVS: 16.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.458

Gene Damage Prediction

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