rs1064793917 — SERPING1

Frameshift deletion in SERPING1 (p.Lys390fs) abolishing C1-inhibitor production — causes hereditary angioedema Type I with recurrent life-threatening swelling attacks via uncontrolled bradykinin release

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SERPING1 c.1169_1175del — A Seven-Base Deletion That Silences C1-Inhibitor

The SERPING1 gene encodes C1-inhibitor (C1-INH)11 C1-inhibitor (C1-INH)
Serpin family G member 1 — a serine protease inhibitor that regulates the complement, contact activation, fibrinolytic, and coagulation pathways, keeping the body's inflammatory cascade under strict control. When C1-INH is absent or non-functional, the contact activation pathway generates bradykinin — a potent peptide that opens vascular endothelial junctions and forces fluid into surrounding tissues. The result is hereditary angioedema (HAE): unpredictable, recurrent episodes of severe swelling affecting the skin, gut, and airway, with laryngeal attacks carrying real mortality risk if untreated.

The c.1169_1175del variant removes seven nucleotides (AGTTCCA) from exon 8 of the SERPING1 coding sequence. This shifts the reading frame starting at codon 390 (lysine, p.Lys390fs) and creates a premature stop codon shortly downstream. The truncated transcript is almost certainly eliminated by nonsense-mediated mRNA decay, producing no functional C1-INH protein from that allele — the molecular hallmark of HAE Type I. HAE affects approximately 1 in 50,000–77,000 people globally22 1 in 50,000–77,000 people globally
Guan et al. 2024 systematic review, 65 studies, 10,310 patients; prevalence range 0.13–1.6 per 100,000 across regions, with no significant ancestry differences.

The Mechanism

C1-INH is the dominant inhibitor of factor XIIa and plasma kallikrein33 factor XIIa and plasma kallikrein
the two key enzymes of the contact activation pathway that ultimately produce bradykinin from high-molecular-weight kininogen, as well as complement proteases C1r and C1s. When one SERPING1 allele carries a frameshift, circulating C1-INH levels fall to roughly 30–50% of normal — insufficient to fully suppress kallikrein activity. Bradykinin surges drive episodes of submucosal and subcutaneous edema44 submucosal and subcutaneous edema
Non-pitting swelling in the deep dermis and submucosa, not at the skin surface — which is why antihistamines and corticosteroids, which target mast-cell-driven allergic edema, are completely ineffective in HAE. Attacks commonly affect the face, hands, genitalia, and gastrointestinal tract (producing abdominal pain that mimics a surgical emergency), and the larynx — where swelling can obstruct the airway within hours.

HAE follows autosomal dominant inheritance55 autosomal dominant inheritance
One mutant allele is sufficient to cause disease — the remaining functional allele cannot compensate for the 50% reduction in C1-INH. Each child of an affected parent has a 50% chance of inheriting the mutation. De novo mutations account for approximately 20–25% of cases, so a negative family history does not exclude the diagnosis.

The Evidence

The mortality data from HAE are stark. A landmark study by Bork et al.66 Bork et al.
Journal of Allergy and Clinical Immunology, 2012 — 728 patients across 182 families found that 70 of 214 deceased patients died from laryngeal asphyxiation. Among those who died of asphyxiation, 63 had never received a HAE diagnosis — they lived on average 31 years shorter than diagnosed HAE patients who died from other causes. The systematic review by Guan et al.77 Guan et al.
Orphanet Journal of Rare Diseases, 2024 — 65 studies, 10,310 patients quantified the overall asphyxiation mortality risk at 8.6%, with a mean diagnostic delay of 3.9 to 26 years. This diagnostic gap is where most preventable deaths occur.

The mutation spectrum of SERPING1 is broad. A Spanish cohort study by López-Lera et al.88 López-Lera et al.
Molecular Immunology, 2011 — 59 families identified 52 distinct mutations, of which 15 (29%) were frameshifts. Frameshift mutations virtually always abolish protein production entirely (Type I HAE) rather than producing a dysfunctional protein (Type II). A Chinese cohort study of 97 HAE patients (Wang et al.99 (Wang et al.
Hereditas, 2022) similarly found frameshifts accounting for 28.9% of SERPING1 mutations, confirming that frameshift variants represent the largest class after missense mutations.

Modern therapies have transformed HAE management. The HELP trial1010 HELP trial
Riedl et al., Allergy, 2020 — lanadelumab subcutaneously every 2–4 weeks showed 85.7–100% of patients achieved ≥50% attack reduction versus 26.8% on placebo, with 37.9–48.1% becoming completely attack-free. The APeX-2 trial1111 APeX-2 trial
Zuraw et al., JACI, 2021 — berotralstat 150 mg daily showed an oral kallikrein inhibitor reduced attacks from 2.35 to 1.31 per month (P<0.001). For acute attacks, icatibant1212 icatibant
Cicardi et al., NEJM, 2010 — FAST-1/2 trials (a bradykinin B2 receptor antagonist) reduced time to symptom relief to 2.0–2.5 hours compared to 4.6–12.0 hours for control.

Practical Actions

The primary priorities for carriers are accurate diagnosis, access to on-demand acute treatment carried at all times, and an individualized prophylaxis plan developed with an HAE specialist. Laryngeal attacks follow a predictable progression: a predyspnea phase averaging 3.7 hours, then a dyspnea phase averaging 41 minutes, then rapid deterioration. Treatment must begin in the predyspnea phase — waiting for dyspnea is dangerous.

Estrogen-containing medications (oral contraceptives, hormone replacement therapy) precipitate and worsen HAE attacks by reducing C1-INH levels and increasing bradykinin production. ACE inhibitors block the enzyme that normally degrades bradykinin, dramatically increasing attack frequency, and are specifically contraindicated. All prescribing clinicians must be informed of the HAE diagnosis before initiating new medications.

Interactions

rs1064793917 is one of three SERPING1 pathogenic frameshift or missense variants in the GeneOps platform (see also rs1064793792 and rs201363394). Each independently causes HAE Type I through C1-INH deficiency. Compound heterozygosity — carrying two different SERPING1 pathogenic variants on opposite chromosomes — produces a phenotype equivalent to homozygosity (essentially complete C1-INH loss), documented in the literature for multiple SERPING1 variant pairs. Family members found to carry pathogenic variants at two independent SERPING1 loci require urgent HAE specialist management equivalent to the homozygous protocols.

Genotype Interpretations

What each possible genotype means for this variant.

II Non-carrier Normal

No SERPING1 c.1169_1175del — normal C1-inhibitor function at this locus

You do not carry the SERPING1 c.1169_1175del frameshift deletion. Both copies of your SERPING1 gene are intact at this position, and C1-inhibitor production from this locus is unaffected. This genotype is found in the vast majority of people — the deletion allele affects roughly 1 in 50,000 individuals globally. Note that many other SERPING1 variants can cause hereditary angioedema; a negative result here does not comprehensively screen for all HAE-causing mutations in this gene.

DI HAE Carrier (Heterozygous) High Risk

One copy of the SERPING1 frameshift — hereditary angioedema Type I

The frameshift at c.1169_1175 almost certainly triggers nonsense-mediated mRNA decay, eliminating protein production from the affected allele entirely. Circulating C1-INH antigen typically falls to 5–30% of normal in Type I HAE (versus 70–135% in unaffected individuals), and functional C1-INH activity is similarly reduced. Without adequate C1-INH, factor XIIa activates plasma kallikrein, which cleaves high-molecular-weight kininogen to release bradykinin. Bradykinin binds B2 receptors on vascular endothelium, opening intercellular junctions and driving fluid into the interstitium — producing characteristic non-pitting edema that does not respond to antihistamines or steroids.

Attacks affect the skin (face, hands, feet, genitalia), gastrointestinal tract (severe colicky abdominal pain with vomiting, frequently misdiagnosed as appendicitis), and the larynx (the most dangerous site — swelling can progress to complete airway obstruction within hours). Attack frequency ranges from monthly in severely affected individuals to a few times per year in mildly affected ones. Trigger factors include physical trauma, surgery, dental procedures, infection, emotional stress, and — importantly in women — estrogen-containing medications.

A systematic review across 10,310 HAE patients found mean diagnostic delay of 3.9–26 years. During the undiagnosed period, patients typically receive multiple ineffective treatments. The HAE asphyxiation mortality risk is 8.6% overall, dropping precipitously once the diagnosis is established and on-demand treatment prescribed.

Current standard of care: - On-demand acute treatment (carried at all times): icatibant (Firazyr, bradykinin B2 antagonist), plasma-derived C1-INH concentrate (Berinert, Haegarda), or recombinant C1-INH (Ruconest) - Long-term prophylaxis (for frequent attackers): lanadelumab (Takhzyro, monoclonal anti-kallikrein) every 2–4 weeks subcutaneously, or berotralstat (Orladeyo, oral kallikrein inhibitor) 150 mg daily - Short-term prophylaxis (before surgical or dental procedures): C1-INH concentrate 1–2 hours before the procedure

DD Homozygous Homozygous

Two copies of the SERPING1 frameshift — very high risk of severe HAE

Homozygosity for a SERPING1 frameshift is expected to eliminate virtually all C1-INH production, producing more severe biochemical deficiency than heterozygosity. C4 complement levels may be persistently low even between attacks (rather than intermittently low), and clinical attacks are typically more frequent and severe. Clinical experience with homozygous HAE-C1-INH is limited to case reports; the most appropriate management mirrors that of severely affected heterozygous carriers with frequent laryngeal attacks.

Long-term prophylaxis is essentially mandatory given the expected attack burden. Lanadelumab (Takhzyro) and berotralstat (Orladeyo) should be discussed with an HAE specialist without delay. On-demand treatment must be available at all times, and at least two doses should be maintained at home and carried when traveling.

Genetic counseling is especially important: a homozygous individual will transmit the deletion to 100% of biological children (making all offspring at minimum heterozygous carriers). If the partner also carries this deletion, 25% of offspring would be homozygous. Preimplantation genetic testing (PGT-M) should be discussed before conception.