rs61750612 — VWF R1853X

VWF R1853X — A Stop Codon That Silences the Clotting Glue

Von Willebrand factor (VWF) is a large glycoprotein that serves two essential roles in hemostasis: it acts as molecular glue that tethers platelets to damaged blood vessel walls, and it escorts coagulation factor VIII through the circulation, protecting it from premature breakdown. Without adequate VWF, even a minor cut or dental procedure can trigger prolonged, difficult-to-control bleeding. The VWF R1853X variant introduces a premature stop codon that truncates the protein at position 1853, eliminating its ability to form the large multimeric structures needed for normal platelet adhesion.

The Mechanism

The VWF gene on chromosome 12 is transcribed from the minus (coding) strand. On the plus strand, the pathogenic change is G→A at position 6,013,544 (GRCh38), which corresponds to a CGA→TGA (Arg→Stop) substitution in codon 1853 of the mature protein. This stop-gained variant¹¹ stop-gained variant
Also called a nonsense mutation; a single base change that converts an amino acid codon into a stop signal, prematurely terminating translation truncates VWF before its C-terminal cystine knot domain, which is essential for dimerization and multimerization. Without intact multimerization, the resulting protein cannot assemble into the ultra-large VWF multimers that are most effective at capturing platelets under high shear flow in arteries and arterioles. In homozygous individuals, essentially no functional VWF is produced, causing von Willebrand disease type 3²² von Willebrand disease type 3
The most severe form of VWD, characterized by near-complete absence of VWF antigen and activity, plus secondary factor VIII deficiency.

The Evidence

The R1853X variant was first documented by Zhang et al. in 1992³³ first documented by Zhang et al. in 1992
Performed at Karolinska Hospital, Stockholm; the study identified nonsense mutations at CGA codons in exons 28, 32, and 45 of the VWF gene in 25 Swedish patients with severe type 3 VWD. The research showed that homozygous carriers exhibited a pronounced bleeding tendency consistent with type 3 disease, while heterozygous relatives showed the milder type 1 phenotype — establishing the codominant dose-response relationship between allele count and disease severity.

The variant was subsequently confirmed as pathogenic in the ThromboGenomics project⁴⁴ ThromboGenomics project
High-throughput sequencing of 2,396 patients with rare hemostatic disorders at University of Cambridge; identified the variant in a European individual through the 3WINTERS-IPS registry. Classification applied ACMG 2015 criteria with PVS1 (null variant in a gene where loss of function is a known disease mechanism), meeting pathogenic threshold.

Type 3 VWD caused by biallelic VWF null mutations is characterized by: VWF antigen below 1 IU/dL (reference ≥50), VWF ristocetin cofactor activity undetectable, and factor VIII activity typically 1–10% of normal due to the loss of VWF's carrier and stabilizing function. Clinically, this produces spontaneous mucosal bleeding (epistaxis, gingival bleeding, menorrhagia), gastrointestinal hemorrhage, and in severe cases joint bleeding (hemarthrosis) resembling hemophilia A — unlike milder VWD types which rarely cause joint bleeds.

Global allele frequency of the A (stop) allele is approximately 0.014% (1 in 7,000 alleles) across gnomAD datasets, making homozygosity (type 3 VWD) vanishingly rare at roughly 1 in 200 million births if Hardy-Weinberg equilibrium holds — consistent with the observed prevalence of severe VWD of about 1 in 1,000,000 in the general population.

Practical Actions

Management depends critically on genotype. Heterozygous carriers (type 1 VWD) have mildly reduced VWF levels and typically require treatment only at hemostatic challenges — surgery, dental procedures, childbirth. [Desmopressin (DDAVP) | A synthetic analog of antidiuretic hormone that causes endothelial cells to release stored VWF; effective in type 1 but not type 3 VWD] can temporarily raise VWF levels 3- to 5-fold in responsive carriers, but its utility in heterozygotes carrying a null allele must be confirmed by a DDAVP challenge test, since approximately 25% of type 1 carriers are non-responsive.

Homozygous R1853X carriers (type 3 VWD) are DDAVP non-responsive — there is no stored VWF to release — and require plasma-derived or recombinant VWF concentrate for any bleeding episode or surgical procedure. The target for treatment is VWF:RCo ≥50 IU/dL (activity) and FVIII ≥50 IU/dL for surgical procedures. Prophylactic VWF concentrate infusions (1-2 times weekly) are used in patients with frequent spontaneous bleeds, particularly joint bleeds.

Interactions

The severity of VWD in R1853X heterozygotes can be modified by blood group ABO — individuals with blood group O have VWF levels roughly 25% lower than non-O individuals, and an O-group R1853X heterozygote may have sufficiently low VWF to present with more severe type 1 phenotype than expected from the single variant alone. This interaction warrants complete VWD panel testing including ABO-adjusted reference ranges.

Compound heterozygosity — carrying R1853X on one chromosome and a different VWF pathogenic variant on the other — produces a type 3-like phenotype even without R1853X homozygosity. Family members of R1853X carriers should therefore be tested not only for R1853X but for the full VWF coding sequence if a severe phenotype is present.