rs61750612 — VWF R1853X

Nonsense mutation creating a premature stop codon at position 1853 of von Willebrand factor; homozygotes develop severe type 3 VWD with essentially absent VWF and require factor replacement, while heterozygotes typically have mild type 1 VWD

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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.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

No VWF R1853X variant — standard von Willebrand factor function from this site

You carry two copies of the common G allele at rs61750612. This is the typical genotype found in the vast majority of the population (over 99.97% of people globally). Your VWF gene does not carry the R1853X stop mutation at this position. You do not have elevated VWD risk from this specific variant.

AA Type 3 VWD Deficient

Two copies of R1853X — severe type 3 von Willebrand disease requiring active factor replacement

Laboratory profile in type 3 VWD caused by biallelic null VWF mutations: - VWF antigen (VWF:Ag): typically <1-3 IU/dL (normal ≥50 IU/dL) - VWF activity (VWF:RCo): undetectable or <3 IU/dL - Factor VIII activity (FVIII:C): 1-10% of normal (secondary deficiency) - VWF multimers: absent on gel electrophoresis

DDAVP (desmopressin) is ineffective in type 3 VWD because there is no stored VWF in endothelial Weibel-Palade bodies to release.

Treatment is with plasma-derived VWF concentrate (e.g., Wilate, Humate-P) or recombinant VWF (Vonvendi/vonicog alfa). Targets: - Minor bleeding/procedures: VWF:RCo ≥50 IU/dL - Major surgery or life-threatening bleeding: VWF:RCo ≥100 IU/dL and FVIII ≥50-100 IU/dL

Prophylactic infusions (typically 40-50 IU/kg VWF concentrate once or twice weekly) are recommended for patients with frequent spontaneous bleeds or joint disease. Monitoring during treatment involves measuring VWF:RCo and FVIII:C levels 15-30 minutes post-infusion and at trough to verify target achievement.

Inhibitor development (anti-VWF antibodies) occurs in approximately 7-9% of type 3 VWD patients receiving VWF concentrate, particularly those with gene deletions. While less common with missense mutations, it can complicate management and requires specialist oversight.

AG R1853X Carrier Carrier

One copy of R1853X — VWF carrier status, typically mild type 1 VWD phenotype

Heterozygous R1853X carriers produce VWF from the intact allele only. Because the truncated protein from the stop allele cannot multimerize normally, functional VWF levels are reduced to approximately 50% of the population mean — though there is significant variability influenced by blood group ABO (O-group lowers VWF further by ~25%), inflammation, estrogen status, and modifier genes.

Laboratory profile typically shows: - VWF antigen (VWF:Ag): 30–70 IU/dL (reference ≥50) - VWF activity (VWF:RCo or VWF:GPIbM): proportionally reduced - Factor VIII activity: mildly reduced if VWF:Ag is very low (VWF carries FVIII) - VWF multimer pattern: normal distribution (type 1, not type 2)

A DDAVP (desmopressin) challenge test is critical for surgical planning: about 75% of type 1 VWD carriers respond with a 3- to 5-fold rise in VWF, making DDAVP an effective pre-procedural option. Non-responders require VWF concentrate instead.

Women of reproductive age are at particular risk: menorrhagia affects up to 60% of women with type 1 VWD, and pregnancy requires specific monitoring and delivery planning given that postpartum VWF levels drop rapidly after delivery.