VWF

von Willebrand factor, the group of Receptor ligands

Basic information

Region (hg38): 12:5948877-6124770

Previous symbols: [ "F8VWF" ]

Links

ENSG00000110799 ∙ NCBI:7450 ∙ OMIM:613160 ∙ HGNC:12726 ∙ Uniprot:P04275 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• von Willebrand disease 2 (Definitive), mode of inheritance: AD
• von Willebrand disease 1 (Supportive), mode of inheritance: AD
• von Willebrand disease type 2A (Supportive), mode of inheritance: AD
• von Willebrand disease type 2B (Supportive), mode of inheritance: AD
• von Willebrand disease type 2M (Supportive), mode of inheritance: AD
• von Willebrand disease type 2N (Supportive), mode of inheritance: AR
• von Willebrand disease 3 (Supportive), mode of inheritance: AR
• von Willebrand disease 1 (Strong), mode of inheritance: AD
• von Willebrand disease 2 (Strong), mode of inheritance: AR
• hereditary von Willebrand disease (Definitive), mode of inheritance: AD
• von Willebrand disease type 2B (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
von Willebrand disease, type 1; von Willebrand disease, type 2A; von Willebrand disease, type 3	AD	Hematologic; Pharmacogenomic	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	Hematologic	315519; 6972630; 6412139; 3116703; 3033024; 3257148; 3258663; 2895123; 2297569; 8456431; 8456432; 8367445; 8052974; 8839833; 9253800; 10444292; 10669167; 11756169; 12649144; 15306670; 17080221; 16889557; 16985174; 17190853; 19085649; 20409624; 22428722; 22458923; 22482515; 22531022; 22530576; 22722677; 22726101; 22823000; 22906074; 22957493; 23034827; 23109357; 23109385

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the VWF gene.

• not provided (57 variants)
• von Willebrand disease type 3 (29 variants)
• von Willebrand disease type 1 (29 variants)
• Hereditary von Willebrand disease (29 variants)
• von Willebrand disease type 2 (26 variants)
• VWF-related disorder (8 variants)
• not specified (4 variants)
• Von Willebrand disease type 2B (3 variants)
• Thrombocytopenia (2 variants)
• Abnormality of coagulation (2 variants)
• Inborn genetic diseases (2 variants)
• Von Willebrand disease type 2A (2 variants)
• Abnormal bleeding (1 variants)
• Reduced quantity of Von Willebrand factor;Reduced von Willebrand factor activity (1 variants)
• von Willebrand disease type 2;von Willebrand disease type 1;von Willebrand disease type 3 (1 variants)
• See cases (1 variants)
• Von Willebrand disease type 2A;von Willebrand disease type 1;von Willebrand disease type 2M (1 variants)
• von Willebrand disease type 2;von Willebrand disease type 3;von Willebrand disease type 1 (1 variants)
• von Willebrand factor Vicenza (1 variants)
• Prolonged bleeding time;Abnormal bleeding (1 variants)
• Abnormality of blood and blood-forming tissues (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the VWF gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		3	26	91	1	121
missense	30	78	460	26	1	595
nonsense	21	16	1			38
start loss						0
frameshift	36	21	1			58
inframe indel	1	5	5			11
splice donor/acceptor (+/-2bp)	10	13	3			26
splice region		1	30	10	2	43
non coding			22	18	78	118
Total	98	136	518	135	80

Highest pathogenic variant AF is 0.0000591

Variants in VWF

This is a list of pathogenic ClinVar variants found in the VWF region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-5949017-A-C			Uncertain significance (Nov 17, 2022)
12-5949023-T-TGCAC		Hereditary von Willebrand disease	Uncertain significance (-)
12-5949034-G-GGGGA		VWF-related disorder	Pathogenic (Apr 19, 2023)
12-5949039-G-C		Thrombocytopenia	Uncertain significance (-)
12-5949041-A-G			Uncertain significance (Jan 04, 2023)
12-5949044-T-TGGGGA			not provided (-)
12-5949046-C-T			not provided (-)
12-5949055-G-T			not provided (-)
12-5949056-C-T		von Willebrand disease type 1	Uncertain significance (Apr 28, 2021)
12-5949079-A-G		not specified • VWF-related disorder	Uncertain significance (Feb 22, 2024)
12-5949091-G-C		Hereditary von Willebrand disease • not specified	Uncertain significance (Jan 05, 2024)
12-5949091-G-T		Inborn genetic diseases	Uncertain significance (Nov 08, 2022)
12-5949112-A-G			Uncertain significance (Feb 09, 2021)
12-5949116-G-A			not provided (-)
12-5949121-G-A		Inborn genetic diseases	Uncertain significance (Feb 23, 2023)
12-5949122-T-C		Inborn genetic diseases	Uncertain significance (Mar 18, 2024)
12-5949124-C-T			Uncertain significance (Jan 09, 2020)
12-5949125-G-A			Uncertain significance (Jan 25, 2018)
12-5949130-G-A			not provided (-)
12-5949131-G-A			Uncertain significance (Nov 07, 2022)
12-5949132-A-G			Likely benign (May 31, 2023)
12-5949134-A-G		von Willebrand disease type 3	Uncertain significance (Nov 01, 2020)
12-5949139-C-G			not provided (-)
12-5949140-A-G		Von Willebrand disease type 2A	Pathogenic (May 01, 2010)
12-5949140-AG-A			not provided (-)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
VWF	protein_coding	protein_coding	ENST00000261405	51	175897

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.22e-25	1.00	125501	0	247	125748	0.000983

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.990	1491	1.60e+3	0.930	0.000102	18429
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00131	0.00130
Ashkenazi Jewish	0.000400	0.000397
East Asian	0.00272	0.00272
Finnish	0.000836	0.000832
European (Non-Finnish)	0.000973	0.000959
Middle Eastern	0.00272	0.00272
South Asian	0.000915	0.000915
Other	0.00164	0.00163

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Human papillomavirus infection - Homo sapiens (human);Platelet Aggregation Inhibitor Pathway, Pharmacodynamics;Blood Clotting Cascade;Focal Adhesion;Dengue-2 Interactions with Complement and Coagulation Cascades;Dengue-2 Interactions with Blood Clotting Cascade;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;PI3K-Akt Signaling Pathway;Complement and Coagulation Cascades;MAP2K and MAPK activation;Disease;Signal Transduction;GRB2:SOS provides linkage to MAPK signaling for Integrins ;p130Cas linkage to MAPK signaling for integrins;Integrin alphaIIb beta3 signaling;GP1b-IX-V activation signalling;Platelet Adhesion to exposed collagen;Platelet Aggregation (Plug Formation);Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;Intrinsic Pathway of Fibrin Clot Formation;Integrin signaling;Hemostasis;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Formation of Fibrin Clot (Clotting Cascade);Signaling by RAS mutants;Signaling by high-kinase activity BRAF mutants;Signaling by moderate kinase activity BRAF mutants;Paradoxical activation of RAF signaling by kinase inactive BRAF;Signaling by BRAF and RAF fusions;Oncogenic MAPK signaling;Diseases of signal transduction (Consensus)

Recessive Scores

• pRec: 0.808

Intolerance Scores

• loftool: 0.0306
• rvis_EVS: 1.04
• rvis_percentile_EVS: 91.14

Haploinsufficiency Scores

• pHI: 0.238
• hipred: Y
• hipred_score: 0.603
• ghis: 0.505

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.867

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Vwf
• Phenotype: digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); immune system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: vwf
• Affected structure: head
• Phenotype tag: abnormal
• Phenotype quality: hemorrhagic

Gene ontology

• Biological process: platelet degranulation;cell adhesion;blood coagulation;blood coagulation, intrinsic pathway;hemostasis;response to wounding;platelet activation;extracellular matrix organization;cell-substrate adhesion;protein homooligomerization
• Cellular component: extracellular region;endoplasmic reticulum;platelet alpha granule;platelet alpha granule lumen;Weibel-Palade body;collagen-containing extracellular matrix;extracellular exosome
• Molecular function: protease binding;integrin binding;extracellular matrix structural constituent;protein binding;collagen binding;immunoglobulin binding;identical protein binding;protein homodimerization activity;protein N-terminus binding;chaperone binding