ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(10); Likely pathogenic(6); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)
Variation ID: 314 Accession: VCV000000314.60
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6019621 (GRCh38) [ NCBI UCSC ] 12: 6128787 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 21, 2014 May 12, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.3797C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Pro1266Leu missense NC_000012.12:g.6019621G>A NC_000012.11:g.6128787G>A NG_009072.2:g.110050C>T LRG_587:g.110050C>T LRG_587t1:c.3797C>T LRG_587p1:p.Pro1266Leu P04275:p.Pro1266Leu - Protein change
- P1266L
- Other names
- p.P1266L
- Canonical SPDI
- NC_000012.12:6019620:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00180 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00084
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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VWF | - | - |
GRCh38 GRCh37 |
1476 | 1530 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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May 1, 2010 | RCV000000342.5 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 1, 2024 | RCV000086676.28 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2023 | RCV000314989.11 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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May 12, 2023 | RCV000853236.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 4, 2022 | RCV002247228.3 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003313771.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2023 | RCV003924788.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disorder
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000380604.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
The VWF c.3797C>T (p.Pro1266Leu) missens variant is present in the A1 domain of the VWF protein. Gain-of-function missense or in-frame insertion or deletion variants in … (more)
The VWF c.3797C>T (p.Pro1266Leu) missens variant is present in the A1 domain of the VWF protein. Gain-of-function missense or in-frame insertion or deletion variants in this essential binding domain are the sole cause of von Willebrand disease (VWD) type 2B (Goodeve 2010). The p.Pro1266Leu missense variant is usually the result of a gene conversion with a nearby VWF pseudogene and may be present with other variants. The p.Pro1266Leu variant has been reported in at least four studies in which it is found in a total of 11 unrelated individuals with VWD, including in three patients in a homozygous state (all of whom carried additional variants), four patients in a heterozygous state (all of whom carried additional variants in cis or trans), and four in a heterozygous state (Holmberg et al. 1993; Gupta et al. 2008; Federici et al. 2009; Kasatkar et al. 2014).The p.Pro1266Leu variant was found to co-segregate with disease in an autosomal dominant pattern in a large family study (Holmberg et al. 1993). Control data are unavailable for this variant, which is reported at a frequency of 0.002572 in the European (Finnish) population of the Exome Aggregation Consortium. Federici et al. (2009) reported that patients carrying the p.Pro1266Leu variant collectively had the lowest bleeding time compared to the other 61 study subjects, as well as one of the lowest bleeding severity scores. Individuals with the p.Pro1266Leu variant are reported to have a normal platelet count, normal platelet morphology, normal VWF protein multimers present in the plasma, but with enhanced platelet aggregation. Functional studies revealed the p.Pro1266Leu variant protein showed levels of protein expression and ability to form dimers comparable to wildtype, but demonstrated platelet aggregation at lower ristocetin concentrations than wildtype, which is consistent with the reported phenotype of the patients (Holmberg et al. 1993). Based on the evidence, the p.Pro1266Leu variant is classified as likely pathogenic for von Willebrand disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Mar 21, 2021)
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criteria provided, single submitter
Method: research
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von Willebrand disease type 1
Affected status: yes
Allele origin:
germline
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Laboratory of Hematology, Radboud University Medical Center
Study: WIN study
Accession: SCV002546291.1 First in ClinVar: Jul 13, 2022 Last updated: Jul 13, 2022 |
Number of individuals with the variant: 2
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Uncertain significance
(Nov 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000491028.5
First in ClinVar: Feb 21, 2014 Last updated: Dec 03, 2022 |
Comment:
Reported (sometimes as P503L due to alternate nomenclature) in multiple unrelated patients from different ethnic backgrounds with von Willebrand disease in published literature (Holmberg et … (more)
Reported (sometimes as P503L due to alternate nomenclature) in multiple unrelated patients from different ethnic backgrounds with von Willebrand disease in published literature (Holmberg et al., 1993; Federici et al., 2009; Casonato et al., 2010; Gupta et al., 2005); Published functional studies suggest this variant may be responsible for enhanced platelet reactivity to lower ristocetin concentrations; however, additional studies are needed to validate the functional effect of this variant in the absence of other VWF variants (Holmberg et al., 1993; Gupta et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16889557, 28980759, 31135071, 30488424, 26827609, 22995991, 8367445, 16985174, 20801902, 18805962, 8486782, 20305138, 29388750, 29924503, 29168270, 31618753, 31980526, 26986123, 28640903, 28971901, 31107984, 29984440, 31532876, 30817071, 34426522, 33556167, 33587123, 33942438, 33807613, 34758185, 31064749, 16115133, 8096943) (less)
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Pathogenic
(Jul 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 2
Affected status: no
Allele origin:
paternal
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921855.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
0103 - Dominant negative, gain of function and loss of function are known mechanisms of disease in this gene and are associated with von Willebrand … (more)
0103 - Dominant negative, gain of function and loss of function are known mechanisms of disease in this gene and are associated with von Willebrand disease (OMIM, PMID: 30488424). (I) 0108 - This gene is associated with both recessive and dominant disease. VWD can be both dominantly and recessively inherited, and is categorised into six different types: 1 (MIM#193400), 2A, 2B, 2M, 2N (MIM#613554) and 3 (MIM#277480). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 19372260). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 19372260). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (232 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (72 heterozygotes, 2 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated D3-A1 junction of the VWA N2 domain (NCBI, PMID: 26986123). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic or pathogenic, and has been observed in many heterozygous individuals with type 2B VWD. It is common for heterozygous individuals to have additional variants in cis, however these variants are often reported as VUS, likely benign and/or benign (ClinVar, PMID: 18805962, 28971901, 30817071, 28640903, 35307943). This variant has also been reported in patients with type 3 VWD in the context of a homozygous gene conversion event, where additional variants including nonsense variants are also present (PMID: 29984440, 31532876, 16115133). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Individuals with this variant have demonstrated enhanced ristocitin-induced platelet aggregation relative to wildtype (PMID: 8486782). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Pro1266Gln)), has been reported as likely pathogenic and pathogenic, and has been identified in multiple heterozygous individuals with type 2B von Willebrand disease (vWD). It is common for these individuals to have additional variants in cis, however these variants are often reported as VUS, likely benign and/or benign (LOVD, ClinVar, PMID: 18805962, 28971901, 30488424, 26986123, 28640903). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Oct 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disorder
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122478.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: VWF c.3797C>T (p.Pro1266Leu) results in a non-conservative amino acid change located in the VWA N-terminal domain (IPR032361) of the encoded protein sequence. Three … (more)
Variant summary: VWF c.3797C>T (p.Pro1266Leu) results in a non-conservative amino acid change located in the VWA N-terminal domain (IPR032361) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 249794 control chromosomes in the gnomAD database, including 1 homozygote. The variant c.3797C>T (legacy name: P503L) has been reported in the literature in several heterozygous individuals affected with Von Willebrand Disease (e.g. Holmberg_1993, Federici_2009, Veyradier_2016, Szederjesi_2020); in general these patients had an increased bleeding tendency, but their symptoms (when present) were considered mild. Several studies noted that the Pro1266Leu variant frequently results from a gene conversion event with a VWF pseudogene (VWFP1) and occurs together with other pseudogene derived variants. Publications reported experimental evidence evaluating an impact on protein function, including protein stability, binding kinetics, platelet reactivity, and demonstrated altered function for the variant protein (or protein domain) carrying the Pro1266Leu variant in isolation (e.g. Holmberg_1993, Legan_2022). The following publications have been ascertained in the context of this evaluation (PMID: 8486782, 18805962, 32573891, 26986123, 36580664). 14 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134898.5
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
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Pathogenic
(Sep 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160172.2
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The VWF c.3797C>T; p.Pro1266Leu variant (rs61749370), also known as Pro503Leu, has been described in the literature in individuals with von Willibrand disease (VWD) type 2B, … (more)
The VWF c.3797C>T; p.Pro1266Leu variant (rs61749370), also known as Pro503Leu, has been described in the literature in individuals with von Willibrand disease (VWD) type 2B, though it is generally reported in individuals with normal VWF multimers (Casonato 2017, Federici 2009, Holmberg 1993, Veyradier 2016, Weiss 1986). This variant has been reported to co-segregate with disease in affected family members (Holmberg 1993, Weiss 1986), and disease is often described as mild (Federici 2009, Holmberg 1993). This variant is also commonly reported in cis to a p.Val1279Ile variant (James 2007). The p.Pro1266Leu variant is reported in ClinVar (Variation ID: 314), and it is found in the Finnish European population with an overall allele frequency of 0.37% (92/25086 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.325). However, both patient samples and purified protein with the p.Pro1266Leu variant exhibit enhanced ristocitin-induced platelet aggregation relative to wildtype, consistent with type 2B VWD (Holmberg 1993, Weiss 1986). Additionally, another variant at this codon (p.Pro1266Gln) has been described in families with VWD and is considered pathogenic (Casonato 2017, Federici 2009). Based on available information, the p.Pro1266Leu variant is considered to be pathogenic. References: Casonato A et al. Type 2B von Willebrand disease with or without large multimers: A distinction of the two sides of the disorder is long overdue. PLoS One. 2017 Jun 22;12(6):e0179566. PMID: 28640903. Federici AB et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood. 2009 Jan 15;113(3):526-34. PMID: 18805962 Holmberg L et al. von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure. J Clin Invest. 1993 May;91(5):2169-77. PMID: 8486782. James PD et al. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007 Jan 1;109(1):145-54. PMID: 17190853. Veyradier A et al. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. Medicine (Baltimore). 2016 Mar;95(11):e3038. PMID: 26986123. Weiss HJ et al. A new von Willebrand variant (type I, New York): increased ristocetin-induced platelet aggregation and plasma von Willebrand factor containing the full range of multimers. Blood. 1986 Jul;68(1):149-56. PMID: 3487353. (less)
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Likely pathogenic
(Dec 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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VWF-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004743917.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The VWF c.3797C>T variant is predicted to result in the amino acid substitution p.Pro1266Leu. (aka VWD2B Malmo/New York). This variant, and a similar variant, p.Pro1266Gln, … (more)
The VWF c.3797C>T variant is predicted to result in the amino acid substitution p.Pro1266Leu. (aka VWD2B Malmo/New York). This variant, and a similar variant, p.Pro1266Gln, have been reported in patients with autosomal dominant VWD types 1 or 2 (type 2B in Veyradier et al. 2016. PubMed ID: 26986123 and Freitas. 2019. PubMed ID: 30817071; aka p.Pro503Leu, type I New York or type II Malmo in Holmberg et al. 1993. PubMed ID: 8486782; Federici et al. 2009. PubMed ID: 18805962; Ahmad et al. 2013. PubMed ID: 23179108). The p.Pro1266Leu and p.Pro1266Gln substitutions are characterized by enhanced ristocetin-induced platelet aggregation (RIPA), low bleeding severity, normal VWF multimer formation, and no thrombocytopenia in most of the patients harboring one of these two variants (Holmberg et al. 1993. PubMed ID: 8486782; Federici et al. 2009. PubMed ID: 18805962). Several patients with one of these variants were shown to have slightly elevated bleeding severity and the p.Pro1266Leu substitution was reported to enhance the VWF—GP1B? protein interaction (Gupta et al. 2005. PubMed ID: 16115133) suggesting that substitutions of p.Pro1266 are unlikely to be benign and are likely to be a primary cause of disease. This variant is reported in 0.37% of alleles in individuals of European (Finnish) descent in gnomAD, however this is a region with high homology to other sites in the genome so allele frequency data may not be representative. This variant is interpreted as likely pathogenic. (less)
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Likely Pathogenic
(Nov 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary von Willebrand disease
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540666.2
First in ClinVar: Apr 09, 2017 Last updated: Apr 20, 2024 |
Comment:
The p.Pro1266Leu variant (also reported in the literature as Pro503Leu) in VWF has been reported in 6 individuals with von Willebrand disease and segregated with … (more)
The p.Pro1266Leu variant (also reported in the literature as Pro503Leu) in VWF has been reported in 6 individuals with von Willebrand disease and segregated with disease in 5 affected individuals from 3 families (Holmberg 1993 PMID: 8486782, Federici 2009 PMID: 18805962, Casonato 2010 PMID: 20305138, Veyradier 2016 PMID: 26986123). It has also been identified in 0.4% (16/3472) of Ashkenazi Jewish chromosomes and 0.3% (38/10620) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org), though this may be due to pseudogene contamination. This variant has also been reported in ClinVar (Variation ID 314). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Patients with this variant had normal plasma and platelet VWF levels, however, had higher bleeding scores than controls (Casonato 2017 PMID: 28640903). Another study found that this variant did not alter the ability to assemble dimeric species but may increase platelet aggregation, though perhaps less than other variants (Holmberg 1993 PMID: 8486782). In summary, this variant meets criteria to be classified as likely pathogenic . ACMG/AMP Criteria applied: PP1_Moderate, PS4_Moderate, PS3_Supporting, PP4. (less)
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Pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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von Willebrand disorder
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899695.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: female
Ethnicity/Population group: European
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Likely pathogenic
(Jun 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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VON WILLEBRAND DISEASE, TYPE 2
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996153.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This variant is a missense variant located in the A1 domain of the von Willebrand factor (VWF) protein. Gain-of-function missense variants in this essential binding … (more)
This variant is a missense variant located in the A1 domain of the von Willebrand factor (VWF) protein. Gain-of-function missense variants in this essential binding domain have been previously reported as causative for von Willebrand disease type 2B (PMID: 28640903). The c.3797C>T (p.Pro1266Leu) variant was found to co-segregate with disease in an autosomal dominant pattern in a large family study (PMID: 8486782). Federici et al. reported that patients carrying the p.Pro1266Leu variant collectively had the lowest bleeding time compared to the other 61 study subjects, as well as one of the lowest bleeding severity scores (PMID: 18805962). Individuals with the p.Pro1266Leu variant are reported to have a normal platelet count, normal platelet morphology, normal VWF protein multimers present in the plasma, but with enhanced platelet aggregation. Functional studies revealed the p.Pro1266Leu variant protein showed levels of protein expression and ability to form dimers comparable to wild-type, but demonstrated platelet aggregation at lower ristocetin concentrations than wildtype (PMID: 8486782, 28640903). The variant is present in the gnomAD database at an allele frequency of 0.08% (234/281180), and includes a report of one homozygous individual. Based on the combined evidence, the variant is classified as likely pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 2
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002506794.1 First in ClinVar: May 12, 2022 Last updated: May 12, 2022 |
Comment:
The VWF c.3797C>T (p.Pro1266Leu, legacy nomenclature p.Pro503Leu) missense variant is present in the A1 domain (exon 28 of 52) of the VWF protein. Gain-of-function missense … (more)
The VWF c.3797C>T (p.Pro1266Leu, legacy nomenclature p.Pro503Leu) missense variant is present in the A1 domain (exon 28 of 52) of the VWF protein. Gain-of-function missense or in-frame insertion or deletion variants in this essential binding domain are causative of von Willebrand disease (VWD) type 2B (PMID:20409624). The p.Pro1266Leu missense variant is usually the result of a gene conversion with a VWF pseudogene and may be present with other variants. The p.Pro1266Leu variant has been reported in multiple studies with unrelated individuals with VWD, in homozygous (all of whom carried additional variants) and in heterozygous state with or without additional variants in cis or trans (PMIDs: 8486782; PMID:18805962; PMID: 24675615; PMID: 18485763; PMID: 20305138). The p.Pro1266Leu variant was found to co-segregate with disease in an autosomal dominant pattern in a large family study (PMID: 8486782). Federici et al. (2009) reported that patients carrying the p.Pro1266Leu variant collectively had the lowest bleeding time compared to the other 61 study subjects, as well as one of the lowest bleeding severity scores (PMID: 18805962). Individuals with the p.Pro1266Leu variant are reported to have a normal platelet count, normal platelet morphology, normal VWF protein multimers present in the plasma, but with enhanced platelet aggregation. Functional studies revealed the p.Pro1266Leu variant protein showed levels of protein expression and ability to form dimers comparable to wildtype, but demonstrated platelet aggregation at lower ristocetin concentrations than wildtype, which is consistent with the reported phenotype of the patients (PMID: 8486782; PMID:28640903). This variant is present in Gnomad v3 at an allele frequency of 0.000880 and has been reported in Clinvar as Pathogenic/ Likely Pathogenic by multiple independent submitters (Variation ID: 314). Based on this evidence, the p.Pro1266Leu variant is classified as Likely Pathogenic. (less)
Clinical Features:
Seizure (present) , Global developmental delay (present) , Hydrocephalus (present) , Cerebral palsy (present) , Cerebral visual impairment (present) , Abnormality of von Willebrand factor … (more)
Seizure (present) , Global developmental delay (present) , Hydrocephalus (present) , Cerebral palsy (present) , Cerebral visual impairment (present) , Abnormality of von Willebrand factor (present) , Scoliosis (present) , Failure to thrive (present) , Intellectual disability (present) (less)
Secondary finding: no
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 1
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002519960.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 2
Affected status: yes
Allele origin:
germline
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002499575.2
First in ClinVar: Apr 23, 2022 Last updated: Sep 17, 2022
Comment:
Submitted to GoldVariant by Kathleen Freson, Center for Molecular and Vascular Biology, Leuven, Belgium
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Clinical Features:
Postpartum bleeding (present) , Thrombocytopenia (present) , Platelet aggregation with low dose ristocetin (present)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Thrombocytopenia
Affected status: yes
Allele origin:
germline
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV004013116.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023
Comment:
Submitted to the GoldVariant database by Kathleen Freson, Center for Molecular and Vascular Biology
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Clinical Features:
Macrothrombocytopenia (present)
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Likely pathogenic
(May 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 2
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175203.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The VWF c.3797C>T variant is classified as LIKELY PATHOGENIC (PM2_supporting, PS4_moderate, PM5, PS3_moderate, PP1_Supporting, PP4) The VWF c.3797C>T variant is a single nucleotide change in … (more)
The VWF c.3797C>T variant is classified as LIKELY PATHOGENIC (PM2_supporting, PS4_moderate, PM5, PS3_moderate, PP1_Supporting, PP4) The VWF c.3797C>T variant is a single nucleotide change in exon 28/52 of the VWF gene, which is predicted to change the amino acid proline at position 1266 in the protein to leucine. The variant is rare in population databases (gnomAD allele frequency = 0.088%, 134 het and 0 hom in 152,126 sequenced alleles) (PM2_supporting). It has been reported multiple times in the literature in affected individuals (PMID: 18805962, 28971901, 30817071, 28640903, 29984440, 31532876) (PS4_moderate). This variant is a novel missense change at an amino acid residue where a different missense change (p.Pro1266Gln) has been seen before (PMID: 18805962) (PM5). Functional studies show a deleterious effect of the variant on protein function (PMID: 8486782, 28640903) (PS3_moderate). The variant has been reported in the literature to segregate with disease in autosomal dominant affected individuals (PMID: 8486782) (PP1_Supporting). The clinical features of this case are highly specific for the VWF gene (Phx of RiCOF, ratio <0.6 and high bleeding score) (PP4). The variant has been reported in dbSNP (rs61749370) and in the HGMD database (CM930727). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 314). (less)
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Pathogenic
(Jan 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246255.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
VWF: PP1:Strong, PM1, PM5, PS3:Moderate, PP4, BP4
Number of individuals with the variant: 3
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Pathogenic
(May 01, 2010)
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no assertion criteria provided
Method: literature only
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VON WILLEBRAND DISEASE, TYPE 2B
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020486.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered … (more)
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated PRO503LEU is now designated PRO1266LEU (P1266L). In affected members of a Swedish family (Holmberg et al., 1986) and a German family with a variant of VWD type 2B (see 613554), Holmberg et al. (1993) identified a heterozygous C-to-T transition in the VWF gene, resulting in a pro503-to-leu (P503L) substitution in the mature subunit. The phenotype was unique in that there was a mild bleeding disorder, and laboratory studies showed that platelets aggregated at much lower ristocetin concentrations than normal. The bleeding time was variously prolonged, and VWF:Ag, VWF activity, and F8 were decreased. All VWF multimers were present, and there was no thrombocytopenia. The defect in this family, inherited as an autosomal dominant trait, resembled that of type 2B because of the response to ristocetin, but differed because all VWF multimers were present. Holmberg et al. (1986) referred to it as 'type 2 Malmo.' Weiss and Sussman (1985) reported a similarly affected family, and referred to this variant as 'type I New York' (Sadler et al., 2006). Wylie et al. (1988) also described this variant and noted that there was no spontaneous aggregation of platelets. Sadler et al. (2006) emphasized that this variant is a form of VWD type 2B with increased sensitivity to ristocetin in vivo. (less)
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Likely pathogenic
(Apr 26, 2022)
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no assertion criteria provided
Method: clinical testing
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von Willebrand disease type 2
Affected status: yes
Allele origin:
germline
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Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Accession: SCV002513392.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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von Willebrand disorder
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002507244.2
First in ClinVar: May 12, 2022 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Academic Unit of Haematology, University of Sheffield
Accession: SCV000118880.1
First in ClinVar: Feb 21, 2014 Last updated: Feb 21, 2014 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Type 2B von Willebrand disease mutations differentially perturb autoinhibition of the A1 domain. | Legan ER | Blood | 2023 | PMID: 36580664 |
von Willebrand factor propeptide missense variants affect anterograde transport to Golgi resulting in ER retention. | Yadegari H | Human mutation | 2021 | PMID: 33942438 |
Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study. | Maron JL | JAMA pediatrics | 2021 | PMID: 33587123 |
von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. | Sadler B | Blood | 2021 | PMID: 33556167 |
Comparison of von Willebrand factor platelet-binding activity assays: ELISA overreads type 2B with loss of HMW multimers. | Szederjesi A | Journal of thrombosis and haemostasis : JTH | 2020 | PMID: 32573891 |
Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing. | Ziats MN | Pediatric research | 2020 | PMID: 31618753 |
Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease. | Ahmed S | Haemophilia : the official journal of the World Federation of Hemophilia | 2019 | PMID: 31532876 |
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
Genetic variants of VWF gene in type 2 von Willebrand disease. | Freitas SDS | Haemophilia : the official journal of the World Federation of Hemophilia | 2019 | PMID: 30817071 |
Type-3 von Willebrand disease in India-Clinical spectrum and molecular profile. | Elayaperumal S | Haemophilia : the official journal of the World Federation of Hemophilia | 2018 | PMID: 29984440 |
Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients. | Borràs N | Haematologica | 2017 | PMID: 28971901 |
Specific electrostatic interactions between charged amino acid residues regulate binding of von Willebrand factor to blood platelets. | Interlandi G | The Journal of biological chemistry | 2017 | PMID: 28924049 |
Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels. | Lavin M | Blood | 2017 | PMID: 28916584 |
A discontinuous autoinhibitory module masks the A1 domain of von Willebrand factor. | Deng W | Journal of thrombosis and haemostasis : JTH | 2017 | PMID: 28692141 |
Type 2B von Willebrand disease with or without large multimers: A distinction of the two sides of the disorder is long overdue. | Casonato A | PloS one | 2017 | PMID: 28640903 |
Phenotypic Parameters in Genotypically Selected Type 2B von Willebrand Disease Patients: A Large, Single-Center Experience Including a New Novel Mutation. | Woods AI | Seminars in thrombosis and hemostasis | 2017 | PMID: 27978591 |
Diagnostic Differentiation of von Willebrand Disease Types 1 and 2 by von Willebrand Factor Multimer Analysis and DDAVP Challenge Test. | Michiels JJ | Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis | 2017 | PMID: 27443694 |
von Willebrand Disease. | Adam MP | - | 2017 | PMID: 20301765 |
von Willebrand disease type 1 mutation p.Arg1379Cys and the variant p.Ala1377Val synergistically determine a 2M phenotype in four Italian patients. | Pagliari MT | Haemophilia : the official journal of the World Federation of Hemophilia | 2016 | PMID: 27785872 |
A novel platelet-type von Willebrand disease mutation (GP1BA p.Met255Ile) associated with type 2B "Malmö/New York" von Willebrand disease. | Lavenu-Bombled C | Thrombosis and haemostasis | 2016 | PMID: 27683759 |
Genotyping might help therapeutic decision-making in patients with von Willebrand disease type 2 B. | Rugeri L | Haemophilia : the official journal of the World Federation of Hemophilia | 2016 | PMID: 27353798 |
A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. | Veyradier A | Medicine | 2016 | PMID: 26986123 |
Role of von Willebrand Factor--A1 Domain Variants P1266L, H1268D, C1272R, and C1272F in VWD: A Molecular Modeling and Simulation Analysis Approach. | Doss CG | Advances in protein chemistry and structural biology | 2016 | PMID: 26827609 |
Higher and lower active circulating VWF levels: different facets of von Willebrand disease. | Casonato A | British journal of haematology | 2015 | PMID: 26456374 |
Evaluation of an heterogeneous group of patients with von Willebrand disease using an assay alternative to ristocetin induced platelet agglutination. | Stufano F | Journal of thrombosis and haemostasis : JTH | 2015 | PMID: 26206100 |
Platelet function analyser (PFA-100) results and von Willebrand factor deficiency: a 16-year 'real-world' experience. | Ardillon L | Haemophilia : the official journal of the World Federation of Hemophilia | 2015 | PMID: 25753785 |
The spectrum of mutations in Southern Spanish patients with von Willebrand disease. | Álvarez-Laderas I | Haemophilia : the official journal of the World Federation of Hemophilia | 2015 | PMID: 25689060 |
Genetic heterogeneity in a large cohort of Indian type 3 von Willebrand disease patients. | Kasatkar P | PloS one | 2014 | PMID: 24675615 |
High-throughput molecular diagnosis of von Willebrand disease by next generation sequencing methods. | Corrales I | Haematologica | 2012 | PMID: 22315491 |
The genetic basis of von Willebrand disease. | Goodeve AC | Blood reviews | 2010 | PMID: 20409624 |
Abnormal VWF modifies megakaryocytopoiesis: studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B. | Nurden P | Blood | 2010 | PMID: 20118404 |
Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. | Federici AB | Blood | 2009 | PMID: 18805962 |
Genetic defects in von Willebrand disease type 3 in Indian and Greek patients. | Gupta PK | Blood cells, molecules & diseases | 2008 | PMID: 18485763 |
Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). | Budde U | Journal of thrombosis and haemostasis : JTH | 2008 | PMID: 18315556 |
Prevalence of type 2b 'Malmö/New York' von Willebrand disease in Italy: the role of von Willebrand factor gene conversion. | Baronciani L | Journal of thrombosis and haemostasis : JTH | 2008 | PMID: 18315546 |
The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. | James PD | Blood | 2007 | PMID: 17190853 |
Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). | Goodeve A | Blood | 2007 | PMID: 16985174 |
Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. | Sadler JE | Journal of thrombosis and haemostasis : JTH | 2006 | PMID: 16889557 |
Gene conversions are a common cause of von Willebrand disease. | Gupta PK | British journal of haematology | 2005 | PMID: 16115133 |
Scientific visits to the Aland Islands. | Blombäck M | Haemophilia : the official journal of the World Federation of Hemophilia | 1999 | PMID: 23401895 |
Multiple substitutions in the von Willebrand factor gene that mimic the pseudogene sequence. | Eikenboom JC | Proceedings of the National Academy of Sciences of the United States of America | 1994 | PMID: 8134377 |
von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure. | Holmberg L | The Journal of clinical investigation | 1993 | PMID: 8486782 |
von Willebrand's disease characterized by increased ristocetin sensitivity and the presence of all von Willebrand factor multimers in plasma: a new subtype. | Wylie B | Pathology | 1988 | PMID: 3259690 |
von Willebrand's disease characterized by increased ristocetin sensitivity and the presence of all von Willebrand factor multimers in plasma. | Holmberg L | Blood | 1986 | PMID: 3488775 |
A new von Willebrand variant (type I, New York): increased ristocetin-induced platelet aggregation and plasma von Willebrand factor containing the full range of multimers. | Weiss HJ | Blood | 1986 | PMID: 3487353 |
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Text-mined citations for rs61749370 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.