rs61750595 — VWF R1659X

Nonsense mutation creating a premature stop codon in von Willebrand factor; heterozygotes have VWD type 1 (partial VWF deficiency) and homozygotes have VWD type 3, the most severe bleeding disorder caused by near-complete absence of VWF

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VWF R1659X — The Nonsense Mutation That Silences von Willebrand Factor

Von Willebrand factor is the body's universal bleeding stop. Released from the walls of blood vessels the moment they are damaged, VWF forms long threads that catch platelets and act as a scaffold for clot formation, while simultaneously carrying and protecting Factor VIII11 Factor VIII
The clotting protein that haemophilia A patients are missing; VWF shields it from premature breakdown in the bloodstream. The VWF gene on chromosome 12 encodes this 2,813-amino-acid multimeric glycoprotein — one of the largest and most structurally complex proteins in human plasma.

The R1659X variant (also called c.4975C>T in transcript notation; the VWF gene is on the minus strand, so the plus-strand change is G→A at chr12:6,018,443) introduces a premature stop codon at amino acid position 1,659, abruptly truncating the protein within its central A2 domain. This is classified as pathogenic by the ClinGen von Willebrand Disease Variant Curation Expert Panel — the highest-confidence tier of genetic classification, supported by nine independent laboratory submissions.

The Mechanism

Normal VWF translation produces the full 2,813-residue precursor, which is then processed, multimerised in the Golgi, and stored in Weibel-Palade bodies ready for release. The R1659X stop codon creates a truncated mRNA transcript that is almost certainly degraded by nonsense-mediated decay (NMD)22 nonsense-mediated decay (NMD)
A cellular quality-control pathway that destroys mRNAs with premature stop codons before they can be translated — meaning the cell produces little or no protein from the affected allele at all, not merely a shorter non-functional protein.

The dose-response is clear and clinically exploited: one functional copy (AG genotype) produces enough VWF for partial function, causing von Willebrand disease type 133 von Willebrand disease type 1
Partial quantitative deficiency of VWF; typically VWF antigen 30–50% of normal with a mild-to-moderate bleeding phenotype. Two non-functional copies (AA genotype, homozygous or compound heterozygous) produce near-zero VWF — the defining feature of VWD type 3, the most severe form of the most common inherited bleeding disorder in the world.

The Evidence

The molecular identification of R1659X dates to 1992, when Zhang et al.44 Zhang et al.
Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I. Am J Hum Genet, 1992. screened all 11 CGA (arginine) codons in the VWF gene of 25 type 3 VWD patients and identified this among the first documented homozygous point mutations causing severe disease. Heterozygous relatives of these patients consistently showed the milder type 1 phenotype — establishing the codominant inheritance pattern.

Population-level confirmation came from Gupta et al. (2008)55 Gupta et al. (2008)
Genetic defects in von Willebrand disease type 3 in Indian and Greek patients. Blood Cells Mol Dis, 2008., who found R1659X to be one of the most frequent individual VWF defects among type 3 VWD patients of Indian and Greek origin, consistent with a mutation that likely arose once and has been propagated in multiple populations by carrier mating.

The variant is listed in ClinVar as pathogenic for hereditary von Willebrand disease (VCV000000297.13), meeting PVS1 (loss-of-function mechanism in VWD) and PP1 (co-segregation with disease across at least two affected families). Finnish patients documented in the ClinGen expert panel submission showed the full expected triad: pronounced bleeding tendency, low VWF antigen, and low Factor VIII levels.

In gnomAD, the A allele frequency is approximately 0.000007 in European non-Finnish populations and close to zero in all other ancestry groups, consistent with a rare pathogenic variant. The global prevalence of VWD type 3 (requiring two pathogenic alleles) is estimated at 1-3 per million.

Practical Actions

For heterozygous carriers (AG): the half-normal VWF level is usually sufficient to prevent spontaneous bleeding but may manifest as heavier-than-usual periods, easy bruising, or prolonged bleeding after surgery or dental procedures. Confirming VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) with a haematologist is recommended before any planned invasive procedure, and desmopressin (DDAVP)66 desmopressin (DDAVP)
A synthetic hormone that releases VWF from endothelial stores; the first-line treatment for type 1 VWD before surgery or dental work can transiently raise VWF levels 2-5 fold in most type 1 carriers, providing adequate haemostasis for minor procedures.

For homozygotes (AA): VWD type 3 requires prophylactic and on-demand treatment with VWF/FVIII concentrate77 VWF/FVIII concentrate
Plasma-derived or recombinant products containing both VWF and Factor VIII, used to restore haemostasis in type 3 VWD. Desmopressin is ineffective because the endothelial VWF stores are absent. Ongoing care at a haemophilia treatment centre with a specialist haematologist is essential.

Both groups should inform all treating clinicians, surgeons, and dentists of the diagnosis before any procedure. Aspirin, NSAIDs, and other antiplatelet agents can significantly worsen bleeding and should be avoided or used only under specialist supervision.

Interactions

Blood group O (rs505922) independently lowers plasma VWF levels by approximately 25% compared to non-O blood types. A type 1 VWD carrier (AG at rs61750595) who also has blood group O may have substantially lower VWF:Ag than expected — the combined effect can push levels into a range that mimics moderate VWD. This interaction is clinically relevant when interpreting VWF laboratory results and when planning haemostatic management.

The Factor II G20210A variant (rs1799963) and Factor V Leiden (rs6025) are pro-thrombotic variants in the same coagulation pathway. While VWD itself is a bleeding disorder, the co-inheritance of a pro-thrombotic variant creates a clinically complex picture that warrants specialist input for any anti-thrombotic or anticoagulant therapy decisions.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

No VWF nonsense mutation — normal von Willebrand factor production

You carry two functional copies of the VWF gene at this position, with no R1659X nonsense mutation present. Your VWF gene is expected to produce the full-length von Willebrand factor protein, supporting normal platelet adhesion and Factor VIII transport. This is the most common genotype, present in more than 99.99% of the population.

AA Homozygous (VWD Type 3) Absent

Two copies of the VWF stop mutation — near-complete VWF absence (type 3 VWD)

VWD type 3 is characterised by VWF:Ag levels below 1–3 IU/dL (essentially undetectable), VWF:RCo unmeasurable, and FVIII:C typically 1–10% of normal (because VWF normally stabilises FVIII against proteolysis). The bleeding phenotype is severe: haemarthroses (joint bleeds), muscle haematomas, mucosal bleeds, and life-threatening haemorrhage following trauma or surgery without treatment. Desmopressin is ineffective — the endothelial stores of VWF that desmopressin releases are absent.

Standard treatment is on-demand and prophylactic infusion of VWF/FVIII concentrate (plasma-derived products such as Humate-P, Alphanate, or Wilate, or recombinant VWF such as Vonvendi/Veyvondi). Secondary prophylaxis (regular infusions 2–3 times per week) is often initiated to prevent joint damage in severely affected patients.

Alloantibody formation (inhibitors) against transfused VWF occurs in approximately 5–10% of type 3 VWD patients and complicates treatment; this is monitored by regular Bethesda assay inhibitor testing.

Genetic counselling is important — both biological parents of a type 3 patient are obligate carriers (VWD type 1), so siblings have a 25% chance of type 3, 50% of type 1, and 25% of being unaffected.

AG Carrier (VWD Type 1) Carrier

One copy of the VWF stop mutation — partial VWF deficiency (type 1 VWD)

VWD type 1 due to a single-copy loss-of-function mutation like R1659X is the mildest form of inherited VWF deficiency. The half-normal VWF level can be transiently boosted by desmopressin (DDAVP), which releases stored VWF from endothelial Weibel-Palade bodies. A desmopressin challenge test — measuring VWF:Ag and VWF:RCo before and 30-60 minutes after a test dose — should be performed at a haematology centre to determine whether you are a desmopressin responder before any planned procedure. Blood group O independently lowers VWF levels by ~25%; if you are blood group O, your baseline VWF may be lower than typical for a single-allele carrier.

Female carriers should discuss implications with a gynaecologist and haematologist jointly, particularly regarding heavy menstrual bleeding, which is often the presenting symptom and is treatable with tranexamic acid or hormonal management in addition to desmopressin.