Von Willebrand & Anticoagulant Proteins

Common 3'UTR variant in VAMP8 that disrupts a microRNA-96 binding site, elevating VAMP8 protein levels in platelets and increasing platelet degranulation — associated with modestly elevated myocardial infarction and noncardioembolic stroke risk

Pathogenic missense variant in the antithrombin III heparin-binding domain; heterozygous carriers have antithrombin deficiency conferring an approximately 14-fold increased risk of venous thromboembolism

Missense variant in antithrombin (SERPINC1) that impairs heparin-catalyzed thrombin inhibition, causing type II reactive-site antithrombin deficiency and approximately 10-fold increased venous thromboembolism risk

Pathogenic missense in antithrombin III; the A allele causes type II heparin-binding-site (HBS) antithrombin deficiency with heterozygotes carrying 3-5x VTE risk and homozygotes facing severe, often childhood-onset thrombophilia

Likely pathogenic missense variant in antithrombin III; the G allele converts Ser148 to Pro, causing type II pleiotropic antithrombin deficiency that reduces both anticoagulant activity and antigen levels, substantially elevating lifetime VTE risk in heterozygous carriers

Pathogenic PROS1 missense variant in the fourth EGF domain of protein S; heterozygous carriers have reduced free protein S activity and a markedly elevated risk of venous thromboembolism consistent with autosomal dominant type I protein S deficiency

Pathogenic missense variant in protein S causing autosomal dominant thrombophilia with significantly elevated venous thromboembolic risk

Pathogenic nonsense variant in protein S that eliminates the anticoagulant cofactor through a premature stop codon, causing autosomal dominant hereditary protein S deficiency and a markedly elevated lifetime risk of venous thromboembolism

Pathogenic PROS1 missense variant in the SHBG-like domain that impairs protein S secretion; heterozygotes have reduced protein S activity and a substantially elevated risk of venous thromboembolism requiring specialist evaluation

Common synonymous variant in the VWF D2/D' domain region; the T allele is part of a haplotype block strongly associated with elevated plasma VWF antigen levels, increasing platelet adhesion efficiency and thrombotic risk, while the C allele is associated with lower circulating VWF

Low-penetrance variant in von Willebrand factor that causes enhanced protein clearance; carriers have a 78-fold higher odds of reduced VWF antigen levels and elevated risk of mild bleeding, though only ~24% of heterozygotes have measurably low VWF

Missense variant in VWF at codon 1381 (Thr→Ala); the Ala allele (C on plus strand) is the global majority allele and is associated with higher circulating von Willebrand factor levels and elevated thrombotic risk

Missense variant that impairs platelet-neutrophil binding and blocks flow-dependent NETosis; carriers of the Q154 (A) allele have ~15–30% reduced VTE risk

Common ADAMTS13 missense variant substituting glutamate for glutamine at position 448; the G allele acts as a context-dependent modifier of ADAMTS13 enzyme function and is associated with higher rates of atrial fibrillation and cerebral ischemic events in coronary syndrome patients

3' UTR variant in the platelet glycoprotein IIIa gene (ITGB3/GPIIIa) that disrupts a microRNA-binding site, increasing ITGB3 expression and platelet activation; the G allele is associated with elevated risk of ischemic stroke outcomes and adverse events on antiplatelet therapy through synergistic platelet receptor gene interactions

Pathogenic missense variant in the VWF D3 domain causing von Willebrand disease type 2A/IIE — the most common D3-cluster mutation — leading to loss of high-molecular-weight multimers, impaired hemostasis, and variable mucocutaneous bleeding

Missense variant in the VWF A3 collagen-binding domain causing isolated collagen-binding deficiency (type 2M von Willebrand disease) — standard VWF panels appear normal while platelet adhesion at injury sites is impaired

Rare pathogenic missense variant in the VWF A3 collagen-binding domain causing isolated collagen-binding deficiency (type 2M/2CB von Willebrand disease) with normal multimers but impaired platelet adhesion to subendothelial collagen

Missense variant in the spacer domain of ADAMTS13 that reduces VWF-cleaving protease activity and, in type 2 diabetics, increases renal and cardiovascular complication risk with preferential benefit from ACE inhibitor therapy

Intronic ADAMTS13 variant modulating plasma ADAMTS13 levels; the G allele confers ~6.7% higher ADAMTS13 concentration, boosting VWF-cleaving capacity and reducing thrombotic risk — AA homozygotes have the lowest genetically determined ADAMTS13 activity

VWF missense variant (R924Q) that reduces von Willebrand factor and Factor VIII levels, particularly in blood group O carriers, increasing bleeding risk when combined with other VWF variants or low-VWF states

Rare missense variant in the PROC gene encoding protein C; the A allele substitutes histidine for arginine at position 42, partially impairing anticoagulant function and increasing venous thromboembolism risk 3-7 fold in heterozygous carriers

Rare pathogenic missense variant in protein S causing hereditary type III protein S deficiency, with carriers at elevated risk for venous thromboembolism and white matter stroke

Pathogenic missense variant in the vitamin K-dependent anticoagulant gene PROS1; homozygotes develop severe neonatal protein S deficiency with life-threatening thrombosis, and heterozygotes carry partial deficiency with meaningfully elevated VTE risk

Missense variant in the VWF D' domain that abolishes high-affinity Factor VIII binding, causing type 2N (Normandy) von Willebrand disease — a recessively-expressed bleeding disorder mimicking mild hemophilia A

Pathogenic missense in the VWF D3 domain that abolishes factor VIII binding; homozygotes and compound heterozygotes develop type 2N von Willebrand disease, presenting as low FVIII with normal VWF antigen and often misdiagnosed as haemophilia A

Pathogenic missense variant in von Willebrand factor A2 domain adjacent to the ADAMTS13 cleavage site; the Asp substitution renders VWF hypersusceptible to proteolysis, depleting high-molecular-weight multimers and causing autosomal dominant type 2A von Willebrand disease with mucocutaneous bleeding

A2 domain missense variant in von Willebrand factor associated with type 2A von Willebrand disease; the proline substitution destabilizes the A2 domain, increasing susceptibility to ADAMTS13 proteolysis and depleting high-molecular-weight multimers required for platelet adhesion

Missense variant in the VWF A2 domain that destabilizes the protein and increases ADAMTS13 cleavage, causing loss of high-molecular-weight multimers and von Willebrand disease type 2A with mucocutaneous bleeding

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

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

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

Pathogenic missense variant in von Willebrand factor causing intracellular retention of the mutant protein; homozygosity causes severe type 3 von Willebrand disease, heterozygous carriers typically have reduced VWF levels and mild bleeding symptoms

Splice donor variant in VWF intron 43 that destroys the canonical GT dinucleotide; predicted high-confidence loss-of-function associated with reduced VWF levels and type 1 von Willebrand disease in heterozygous carriers

Missense variant in von Willebrand factor (p.Asp141Gly) associated with type 1 von Willebrand disease; heterozygous and homozygous carriers may have reduced VWF activity and increased bleeding tendency requiring hematology evaluation

Nonsense mutation creating a premature stop codon in von Willebrand factor; null allele associated with von Willebrand disease

Pathogenic missense variant in the VWF propeptide D2 domain that introduces an aberrant N-glycosylation site, disrupting VWF multimerization and Weibel-Palade body storage; heterozygous carriers have type 2A von Willebrand disease with qualitative VWF deficiency and variable bleeding risk

Pathogenic missense variant in the VWF propeptide D2 domain that prevents high molecular weight multimer assembly in the Golgi apparatus; homozygous carriers develop von Willebrand disease type 2A with mucocutaneous bleeding, while heterozygotes are typically unaffected

Missense variant in the endothelial protein C receptor gene that increases EPCR shedding, paradoxically raising plasma protein C levels while reducing endothelial anticoagulant activity and increasing VTE risk