rs61750591 — VWF c.4944del

A frameshift deletion in VWF that truncates von Willebrand factor from position 1649; heterozygous carriers are at risk for type 1 von Willebrand disease with reduced VWF levels and mucocutaneous bleeding, most prevalent in Northern European populations

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VWF c.4944del — A Frameshift That Silences von Willebrand Factor

Von Willebrand factor is the molecular bridge between injury and clot. When a blood vessel tears, VWF multimers11 VWF multimers
Giant protein complexes assembled in endothelial cells and megakaryocytes; circulating forms are anchored to collagen at the injury site unspooling from the vessel wall snag passing platelets, holding them in place until a stable clot forms. Without enough VWF, platelets arrive but can't stick — and minor cuts, dental procedures, or surgery become sources of prolonged, difficult-to-stop bleeding. The c.4944del variant deletes a single adenine from the VWF coding sequence, shifting the reading frame at codon 1649 and generating a premature stop signal that destroys a large portion of the mature protein.

The Mechanism

VWF spans 53 exons22 53 exons
VWF is one of the largest genes in the genome at ~178 kb on chromosome 12p13 (gene located on the minus strand). The c.4944del deletion falls in exon 28 of the canonical transcript (NM_000552.5), removing one adenine at coding position 4944 and creating a p.Ile1649fs frameshift. This disrupts the downstream D4 and C domains of the VWF preproprotein — regions critical for multimerisation and platelet GPIbα binding.

A key finding from functional studies is that the aberrant mRNA remains stable33 the aberrant mRNA remains stable
Mohlke et al. 1996 (PMID 8857958) showed mRNA from the deleted allele is not degraded by nonsense-mediated decay, unlike many other frameshift alleles rather than being cleared by nonsense-mediated decay. The truncated protein is synthesised but retained within the endoplasmic reticulum — it cannot undergo normal propeptide processing or multimerisation, and is therefore not secreted. Critically, the truncated VWF does not exert a dominant-negative effect on protein from the intact allele: wild-type VWF from the normal chromosome can still assemble and be secreted normally. This means the disease mechanism is purely quantitative (haploinsufficiency) — the cell produces only half as much functional VWF as normal. The result in heterozygotes is reduced circulating VWF levels (typically 20–50% of the normal range), the hallmark of type 1 von Willebrand disease.

In the rare homozygous state, no functional VWF is produced at all, collapsing VWF levels to near zero and producing the severe bleeding phenotype of type 3 VWD44 type 3 VWD
Type 3 VWD has an estimated prevalence of 1–3 per million; heterozygous parents of type 3 children are typically asymptomatic or have mild type 1.

The Evidence

This frameshift mutation (or close variants in the same exon) has been identified repeatedly across Northern European populations with VWD type 3. Schneppenheim and colleagues55 Schneppenheim and colleagues
Schneppenheim R et al., Hum Genet, 1994 identified a deltaC mutation in VWF exon 18 as "the most common molecular defect in German patients with VWD type III," detecting it in five unrelated families with distinct haplotypes — pointing to recurrent de novo mutation rather than a single ancestral founder.

A follow-up functional study by Mohlke and colleagues66 Mohlke and colleagues
Mohlke KL et al., Br J Haematol, 1996 confirmed the mechanistic picture: the frameshift allele produces stable mRNA but misfolded protein that is retained and degraded intracellularly. Because the truncated protein does not interact with wild-type VWF, heterozygous carriers experience simple haploinsufficiency — reduced synthesis, not a structurally abnormal multimer pattern. This is important clinically: it means the bleeding phenotype in heterozygotes is driven entirely by VWF quantity, and therapeutic approaches that raise VWF levels (desmopressin, VWF concentrate) are appropriate.

Atiq et al. 202277 Atiq et al. 2022
A study of 390 well-characterised Dutch VWD patients in the WiN cohort confirmed that VWF frameshift and nonsense variants in type 1 VWD patients produce disease through reduced synthesis/secretion rather than the accelerated clearance mechanism seen in most missense variants. Type 1 patients with molecular-confirmed VWF variants show "clearly distinct" clinical features — earlier diagnosis, lower VWF antigen levels, and more pronounced bleeding symptoms — compared to type 1 patients without a detected VWF variant.

Practical Implications

For heterozygous carriers, the central clinical question is whether circulating VWF levels are sufficiently reduced to cause clinically relevant bleeding. VWF levels vary substantially even among carriers of the same mutation, influenced by blood type (O blood type reduces VWF levels by ~25%), age, and other modifiers. Confirming VWF antigen level, VWF activity (ristocetin cofactor assay), and factor VIII level provides the quantitative foundation for clinical management. Most heterozygotes will have VWF levels in the 30–60% range (normal 50–200%), placing them in the type 1 or low-VWF category. Bleeding symptoms in this range are primarily mucocutaneous — nosebleeds, easy bruising, heavy menstrual bleeding, and prolonged bleeding after dental extractions or surgery.

Desmopressin (DDAVP) is the first-line treatment for most type 1 VWD patients with this haploinsufficiency mechanism: it triggers endothelial cells to release stored VWF from Weibel-Palade bodies, temporarily raising plasma VWF 2–4 fold. A formal desmopressin challenge test at a haemostasis centre establishes individual responsiveness and the duration of effect before any elective procedure.

Interactions

The c.4944del frameshift interacts with [ABO blood group | O blood type reduces VWF antigen levels by approximately 25% compared to non-O blood types through altered VWF glycosylation and increased clearance] — carriers with blood type O may have VWF levels that fall below the 30% diagnostic threshold for type 1 VWD even if they are mildly symptomatic. Conversely, blood type A, B, or AB can partially compensate for the haploinsufficiency, keeping measured VWF levels in a borderline range despite the same genotype. This VWF × ABO interaction is why VWF level measurement and bleeding history together — rather than genotype alone — drive management decisions.

Women with this variant face compounded risk during menstruation, pregnancy, and delivery. VWF levels rise naturally during pregnancy (sometimes normalising in heterozygotes) but fall rapidly postpartum, creating a window of heightened bleeding risk in the hours after delivery.

Genotype Interpretations

What each possible genotype means for this variant.

II Non-carrier Normal

No VWF deletion — normal von Willebrand factor production from both alleles

You carry two intact copies of the VWF gene at this position: neither allele has the c.4944del frameshift deletion. Your von Willebrand factor is produced at full synthetic capacity from both chromosomes. This is the typical genotype found in the vast majority of the population worldwide. The c.4944del variant is exceedingly rare globally (about 1 in 20,000 chromosomes), with the highest prevalence in Northern European populations.

DI VWF Carrier Carrier

One copy of the c.4944del frameshift — reduced VWF production and type 1 VWD risk

The VWF c.4944del frameshift removes one adenine at coding position 4944, disrupting the reading frame from isoleucine 1649 onward. The resulting truncated mRNA is not degraded by the cell — it remains stable and is translated — but the truncated protein cannot complete normal propeptide cleavage or multimerisation. It is retained and degraded in the endoplasmic reticulum without being secreted. Crucially, it does not interfere with the normal VWF produced by your intact allele. The disease mechanism is therefore pure haploinsufficiency: the intact allele produces its full complement of functional VWF multimers, but there is only one copy instead of two.

Clinical expression varies. Blood type O independently reduces VWF levels by about 25%, so carriers with O blood type are more likely to fall below the diagnostic threshold of 30% VWF activity, and may have more severe symptoms. Non-O carriers (types A, B, AB) sometimes have VWF levels that hover near or above 50%, qualifying as "low VWF" rather than type 1 VWD, with milder bleeding symptoms. Women have additional risk windows during heavy menstruation and in the postpartum period (VWF falls rapidly after delivery despite rising during pregnancy). Stress, inflammation, and exercise transiently raise VWF, so levels tested during an acute illness may appear falsely normal.

The key diagnostic tests are VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo or VWF:GPIbM), and factor VIII:C. A full haemostasis panel at a specialist centre should precede any elective procedure.

DD Homozygous Homozygous

Two copies of the c.4944del deletion — severe VWF deficiency consistent with type 3 von Willebrand disease

Both VWF alleles carry the c.4944del frameshift, abolishing secreted VWF production entirely. Without VWF to carry and protect factor VIII, factor VIII levels also fall substantially — to 1–10% in many type 3 patients — adding a secondary coagulation factor deficiency on top of the primary platelet adhesion defect. The result is a combined haemostatic failure resembling moderate haemophilia A in terms of joint and muscle bleeding risk, in addition to the severe mucocutaneous bleeding typical of VWD.

Frameshift mutations in compound heterozygous or homozygous form in VWF are well-documented causes of type 3 VWD in European populations. Parents of type 3 patients are typically heterozygous carriers with mild type 1 or low-VWF phenotypes. A small proportion of type 3 VWD patients develop inhibitory antibodies (alloantibodies) against transfused VWF — a rare but serious complication that makes standard replacement therapy ineffective.

Treatment for type 3 VWD requires VWF/factor VIII concentrate (not DDAVP, since there is no stored VWF to release). Patients should be managed at a specialised haemophilia treatment centre with 24-hour access to haematology support.