rs61750591 — VWF c.4944del

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.