VWF
protein-codingvon Willebrand factor, the group of Receptor ligands
Gene summary
This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]
- F8VWF
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~175.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010191
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015628
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013304
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008668
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010191
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015630
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015629
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019565
Submitter: ClinGen
von Willebrand disease (VWD) was first described by Erik von Willebrand in 1926, and is characterized by mucosa-associated bleeding and bleeding after trauma or surgery. There are several (sub)types of VWD that can be classified on the basis of phenotypic characteristics, caused by either quantitative (type 1 and 3) or qualitative (type 2) defects of VWF. The relationship of VWF to autosomal dominant VWD was first determined in 1988 by identification of a gross gene deletion (Ngo et al., 1988; PMID: 3258663) and through linkage analysis (Verweij et al., 1988; PMID: 2895123). In 1989, the first variants were identified in patients by Ginsburg et al. (PMID: 2786201). More than 700 unique variants have been reported in humans (EAHAD Coagulation Factor Variant Databases), consisting of predominantly missense variants as well as nonsense, small deletions or insertions, and splice variants (reviewed in PMID: 28987708). Some patients with type 1 VWD may have heterozygous VWF null alleles, but usually these patients carry heterozygous missense variants. The qualitative VWF defects in type 2 VWD are also mainly caused by missense variants. The severe quantitative VWF deficiency as seen in type 3 VWD is usually caused by genetic defects in the VWF gene leading to homozygous or compound heterozygous VWF null alleles (such autosomal recessive cases have been included in this curation as noted in the scoring explanations). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Twenty-two unique variants from 21 probands in 8 publications were curated (PMIDs: 1415226, 26088471, 8622978, 23496210, 2786201, 8839833, 19566550, 20586924). Variants in this gene segregated with disease in 29 additional family members (PMIDs: 1415226, 8839833, 19566550). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. Experimentally, this gene-disease relationship is supported by the function of vWF in platelet adhesion, via collagen and platelet binding (PMIDs: 6809414, 108291), which is consistent with the prolonged bleeding associated with VWD. Alteration of this function has been observed in both patient (PMID: 8435340) and non-patient cells (PMID: 20586924) which exhibit loss of platelet adhesion. Further support is provided by several mouse systems, including a null mouse with extensive bleeding, consistent with type 3 VWD (PMID: 9689113), and hydrodynamic expression of VWD variants in the VWF-/- mice (PMIDs: 22372972, 21346256, PMID: 18487513) which recapitulate many features of types 1 and 2 VWD. In summary VWF is definitively associated with autosomal dominant von Willebrand disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, VWF in relation to type 2B VWD has been described as a distinct form of VWD (PMID: 6767976) and is assessed separately from the additional forms of hereditary von Willebrand disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms (gain of function in type 2B versus loss of function in types 1, 2A, 2M, 2N, and 3) and phenotypic variability (type 2B has the unique phenotypes of thrombocytopenia, increased platelet volume, and enhanced ristocetin-induced platelet aggregation). Therefore, we have split curations for the disease entities hereditary von Willebrand disease and von Willebrand disease type 2B.
Inheritance Pattern: AD
Disease ID:MONDO:0013304
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0015631
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015629
Submitter: ClinGen
von Willebrand disease type 2B (VWD2B) was first described as a distinct form of VWD by Rufferi et al., 1980 (PMID: 6767976). Patients often have a variable degree of thrombocytopenia and present with a prolonged bleeding time commonly triggered by trauma, surgery, dental work or delivery. VWD2B is characterized by an enhanced ristocetin-induced platelet aggregation in platelet-rich plasma. The relationship of VWF to autosomal dominant VWD2B was first reported through linkage analysis in 1989 (Ewenstein et al., 1989; unpublished abstract). In April 1991, the first variants were identified in patients by Randi et al. (PMID: 2010538), Cooney et al. (PMID: 1672694), and Ware et al. (PMID: 2011604). At least 43 unique variants have been reported in humans (PMID: 28987708), all of which occur in exon 28 of VWF and consist almost entirely of missense variants (with the exception of one single amino acid duplication). The mechanism for disease is gain of function; vWF functions as an adhesive protein essential for binding platelets (via GPIb/IX) to both subendothelial collagen and to other platelets. VWD2B mutations result in increased von Willebrand factor (VWF) binding to platelet GPIb receptors, causing increased platelet clearance and preferential loss of high molecular weight VWF multimers (reviewed in PMID: 28987708) as well as defective proplatelet formation (PMIDs:16720832 and 27734030). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Thirteen unique variants from 13 probands in 9 publications were curated (PMIDs: 1672694, 1419803, 8123843, 8547152, 9858249, 1373334, 8376405, 2010538, 2011604). Variants in this gene segregated with disease in 16 additional family members (PMIDs: 2010538, 8376405, 1373334, 9858249, 8547152, 8123843). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. Experimentally, this gene-disease relationship is supported by the function of vWF in platelet binding (PMID: 108291), which is consistent with the prolonged bleeding associated with VWD2B. Further support is provided by several mouse systems, including hydrodynamic expression of VWD2B variants in VWF-/- mice (PMIDs: 20371742 and 20200350) and a knock-in mouse model, which recapitulate many features of VWD2B (PMID: 27212476). In summary VWF is definitively associated with autosomal dominant von Willebrand disease type 2B. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, VWF in relation to type 2B VWD has been described as a distinct form of VWD (PMID: 6767976) and is assessed separately from the additional forms of hereditary von Willebrand disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms (gain of function in type 2B versus loss of function in types 1, 2A, 2M, 2N, and 3) and phenotypic variability (type 2B has the unique phenotypes of thrombocytopenia, increased platelet volume, and enhanced ristocetin-induced platelet aggregation). Therefore, we have split curations for the disease entities hereditary von Willebrand disease and von Willebrand disease type 2B.
Inheritance Pattern: AD
Disease ID:MONDO:0008668
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013304
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013304
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008668
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic; Pharmacogenomic
Rationale: There are a number of treatments depending on the subtype of disease; Treatments include control of severe bleeding episodes (eg, with IV infusion of plasma-derived clotting factor, or IV/SQ desmopressin), as well as fibrinolytic inhibitors and hormones for menorrhagia; Primary prevention can be instituted via prophylactic VWF/FVIII infusions; Among a number of important preventive measures, specific medications should be avoided, including ASA, clopidogrel, NSAIDS
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to VWF variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000552.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 3 | 37 | 164 | 5 | 211 |
| missense | 59 | 145 | 977 | 48 | 5 | 1234 |
| nonsense | 63 | 27 | 17 | 107 | ||
| start loss | 0 | |||||
| frameshift | 79 | 51 | 26 | 156 | ||
| splice donor/acceptor (+/-2bp) | 23 | 30 | 39 | 92 | ||
| Total | 226 | 256 | 1096 | 212 | 10 | 1800 |
Highest pathogenic variant AF is 0.0049559725
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000543.3 | 51 | MANE Select | |
| Ensembl | ENSP00000261405.5 | 51 | MANE Select | |
| Ensembl | ENSP00000461331.1 | 2 | Standard | |
| Ensembl | ENSP00000459134.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| vwf | Danio rerio | Structure: head Quality: hemorrhagic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Complement and coagulation cascades - Homo sapiens (human)
- Platelet activation - Homo sapiens (human)
- ECM-receptor interaction - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
Biological Process
- platelet degranulation
- cell adhesion
- blood coagulation
- blood coagulation, intrinsic pathway
- hemostasis
Molecular Function
- protease binding
- integrin binding
- extracellular matrix structural constituent
- protein binding
- collagen binding
Cellular Component
- extracellular region
- endoplasmic reticulum
- platelet alpha granule
- platelet alpha granule lumen
- Weibel-Palade body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261405
- Coding exons
- 51
- Length
- 175897
- Individuals with no LoFs
- 125501
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 247
- Defined
- 125748
- p
- 0.000983
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.990 | 1491 | 1.60e+3 | 0.930 | 0.000102 | 18429 |
| Missense (PolyPhen) | 538 | 608.65 | 0.88392 | 6920 | ||
| Synonymous | -1.88 | 728 | 666 | 1.09 | 0.0000458 | 5440 |
| Loss of Function | 5.54 | 64 | 133 | 0.481 | 0.00000695 | 1590 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00093 | 0.00092 | rare |
| Latino/Admixed American | 0.00038 | 0.00038 | rare |
| Ashkenazi Jewish | 0.00040 | 0.00040 | rare |
| East Asian | 0.0027 | 0.0027 | notable |
| Finnish | 0.00084 | 0.00083 | rare |
| European (Non-Finnish) | 0.00097 | 0.00096 | rare |
| South Asian | 0.00092 | 0.00091 | rare |
| Other | 0.0016 | 0.0016 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V. Also acts as a chaperone for coagulation factor VIII, delivering it to the site of injury, stabilizing its heterodimeric structure and protecting it from premature clearance from plasma.;
- Disease
- DISEASE: von Willebrand disease 1 (VWD1) [MIM:193400]: A common hemorrhagic disorder due to defects in von Willebrand factor protein and resulting in impaired platelet aggregation. Von Willebrand disease type 1 is characterized by partial quantitative deficiency of circulating von Willebrand factor, that is otherwise structurally and functionally normal. Clinical manifestations are mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. {ECO:0000269|PubMed:10887119, ECO:0000269|PubMed:11698279}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: von Willebrand disease 2 (VWD2) [MIM:613554]: A hemorrhagic disorder due to defects in von Willebrand factor protein and resulting in altered platelet aggregation. Von Willebrand disease type 2 is characterized by qualitative deficiency and functional anomalies of von Willebrand factor. It is divided in different subtypes including 2A, 2B, 2M and 2N (Normandy variant). The mutant VWF protein in types 2A, 2B and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind factor VIII. Clinical manifestations are mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. {ECO:0000269|PubMed:12406074, ECO:0000269|PubMed:1409710, ECO:0000269|PubMed:1419803, ECO:0000269|PubMed:1419804, ECO:0000269|PubMed:1420817, ECO:0000269|PubMed:1429668, ECO:0000269|PubMed:1672694, ECO:0000269|PubMed:1673047, ECO:0000269|PubMed:1729889, ECO:0000269|PubMed:1761120, ECO:0000269|PubMed:1832934, ECO:0000269|PubMed:1906179, ECO:0000269|PubMed:2010538, ECO:0000269|PubMed:2011604, ECO:0000269|PubMed:21592258, ECO:0000269|PubMed:2786201, ECO:0000269|PubMed:7620154, ECO:0000269|PubMed:7734373, ECO:0000269|PubMed:7789955, ECO:0000269|PubMed:8011991, ECO:0000269|PubMed:8123843, ECO:0000269|PubMed:8123844, ECO:0000269|PubMed:8338947, ECO:0000269|PubMed:8348943, ECO:0000269|PubMed:8376405, ECO:0000269|PubMed:8435341, ECO:0000269|PubMed:8486782, ECO:0000269|PubMed:8547152, ECO:0000269|PubMed:8622978}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: von Willebrand disease 3 (VWD3) [MIM:277480]: A severe hemorrhagic disorder due to a total or near total absence of von Willebrand factor in the plasma and cellular compartments, also leading to a profound deficiency of plasmatic factor VIII. Bleeding usually starts in infancy and can include epistaxis, recurrent mucocutaneous bleeding, excessive bleeding after minor trauma, and hemarthroses. {ECO:0000269|PubMed:10887119, ECO:0000269|PubMed:7989040, ECO:0000269|PubMed:8088787}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.808
Intolerance Scores
- LoFtool
- 0.0306
- RVIS EVS
- 1.04
- RVIS percentile EVS
- 91.14
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.867
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |