ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.5191T>A (p.Ser1731Thr)
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.
Likely pathogenic(2); Uncertain significance(6); Likely benign(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.5191T>A (p.Ser1731Thr)
Variation ID: 100420 Accession: VCV000100420.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6016636 (GRCh38) [ NCBI UCSC ] 12: 6125802 (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 25, 2014 May 12, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.5191T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Ser1731Thr missense NC_000012.12:g.6016636A>T NC_000012.11:g.6125802A>T NG_009072.2:g.113035T>A LRG_587:g.113035T>A LRG_587t1:c.5191T>A LRG_587p1:p.Ser1731Thr - Protein change
- S1731T
- Other names
- -
- Canonical SPDI
- NC_000012.12:6016635:A:T
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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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00101
Exome Aggregation Consortium (ExAC) 0.00119
Trans-Omics for Precision Medicine (TOPMed) 0.00125
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00131
The Genome Aggregation Database (gnomAD), exomes 0.00157
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
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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 |
1473 | 1527 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Sep 1, 2023 | RCV000086830.28 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000343743.7 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV000826083.12 | |
Benign (1) |
no assertion criteria provided
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Apr 26, 2022 | RCV002243746.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 23, 2024 | RCV003952537.1 |
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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Uncertain significance
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand Disease
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000380593.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The c.5191T>A (p.Ser1731Thr) variant has been reported in three studies in which it is found in at least four patients in a heterozygous state (Ribba … (more)
The c.5191T>A (p.Ser1731Thr) variant has been reported in three studies in which it is found in at least four patients in a heterozygous state (Ribba et al. 2001, Riddell et al. 2009, Veyradier et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00205 in the European (Non-Finnish) population from the Exome Sequencing Project. This frequency is high in comparison to disease prevalence, but may be explained by a milder phenotype or reduced penetrance. Functional studies including expression of the variant in COS-7 cells demonstrated significantly decreased binding of the variant protein to collagen. Analysis in HEK293T cells showed the p.Ser1731Thr variant affects binding to collagen type I but not type III. Additional functional studies utilizing mouse models, HEK293T cell constructs, flow chamber analysis, and collagen thin films in flow assays support normal expression but reduced collagen binding of the p.Ser1731Thr variant (Flood et al. 2010; Shida et al. 2014; Hansen et al. 2011). Based on the limited number of cases but with supporting functional data, the p.Ser1731Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for von Willebrand disease. (less)
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Uncertain significance
(Aug 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002066513.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the VWF gene demonstrated a sequence change, c.5191T>A, in exon 30 that results in an amino acid change, p.Ser1731Thr. This sequence … (more)
DNA sequence analysis of the VWF gene demonstrated a sequence change, c.5191T>A, in exon 30 that results in an amino acid change, p.Ser1731Thr. This sequence change has been described in the gnomAD database with a frequency of 2.1% in Ashkenazi Jewish subpopulation (dbSNP rs61750603). This sequence change has been previously described in the heterozygous states in individuals and families with von Willebrand disease (PMIDs: 11583318, 26986123, 19687512, 28971901). The p.Ser1731Thr change affects a highly conserved amino acid residue located in the A3 domain of the VWF protein. Functional studies show p.Ser1731Thr disrupts the binding of VWF to collagen (PMIDs: 11583318, 19687512, 20345715). Due to the lack of sufficient evidence, the clinical significance of the p.Ser1731Thr change remains unknown at this time. (less)
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Uncertain significance
(Aug 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004037805.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: VWF c.5191T>A (p.Ser1731Thr) results in a conservative amino acid change located in the third VWF type A (A3) domain (IPR002035), which is the … (more)
Variant summary: VWF c.5191T>A (p.Ser1731Thr) results in a conservative amino acid change located in the third VWF type A (A3) domain (IPR002035), which is the main binding site for collagens type I and III (UniProt) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 251490 control chromosomes in the gnomAD database, including 1 homozygote. However, in certain subpopulations, e.g. in the Ashkenazi Jewish the variant was found at a much higher allele frequency (i.e. 2.1%). The observed relatively high frequency, together with the homozygous occurrence, might indicate a benign nature for the variant, or alternatively the variant might represent a hypomorphic allele associated with a milder phenotype / reduced penetrance. The variant, c.5191T>A, has been reported in the literature in multiple heterozygous individuals affected with Von Willebrand Disease (e.g. Ribba_2001, Riddell_2009, Veyradier_2016, Borras_2017, Maas_2022), and in a homozygous individual with Glanzmann thrombasthenia (Owaidah 2019). However, in at least one family the variant was also observed in asymptomatic younger family members (Riddell_2009), although they also displayed the biochemical phenotype (i.e. decresed VWF binding to type I collagen; see below). Furthermore, in one of these reported cases a co-occurring pathogenic variant could explain the phenotype (Borras_2017). Several publications reported experimental evidence evaluating an impact on protein function, and in general demonstrated reduced binding to collagen type I, with mostly unaffected binding to collagen type III (e.g. Ribba_2001, Riddell_2009, Flood_2010, Shida_2014, Posch_2018). This finding was confirmed by utilizing a knock-in mouse model (Shida_2014), however authors of the study concluded that mice were still able to initiate platelet adhesion and thrombus formation in their model, demonstrating an important role for collagen-independent pathway(s) of primary hemostasis that likely contribute to the mild bleeding phenotype in patients with VWF collagen-binding mutations. The following publications have been ascertained in the context of this evaluation (PMID: 11583318, 19687512, 26986123, 28971901, 30792900, 20345715, 25051961, 29604837, 34758185). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. In conclusion, the variant might represent a relatively frequent hypomorphic allele with reduced penetrance, and seems to be associated with a well-defined biochemical phenotype, however the clinical relevance of these in vitro results is not clear. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004243459.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Uncertain significance
(Mar 20, 2020)
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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: SCV001470133.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Likely pathogenic
(Aug 18, 2023)
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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: SCV000322002.9
First in ClinVar: Feb 25, 2014 Last updated: Sep 14, 2023 |
Comment:
Published functional studies including in vitro collagen binding assays showed a reduction in binding to both type I and type III collagen (Flood et al., … (more)
Published functional studies including in vitro collagen binding assays showed a reduction in binding to both type I and type III collagen (Flood et al., 2010; Shida et al., 2014); This variant is associated with the following publications: (PMID: 21967679, 25662333, 25051961, 19506356, 19687512, 26986123, 16870550, 30046704, 31605304, 32394456, 24385719, 23406206, 18036186, 23216583, 32998182, 19630771, 34426522, 20345715, 30792900, 29924855, 11583318, 34758185, 34708896, 37163579) (less)
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Likely pathogenic
(Jan 23, 2024)
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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: SCV004774522.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The VWF c.5191T>A variant is predicted to result in the amino acid substitution p.Ser1731Thr. This variant has been reported previously to reduce binding between VWF … (more)
The VWF c.5191T>A variant is predicted to result in the amino acid substitution p.Ser1731Thr. This variant has been reported previously to reduce binding between VWF protein and different collagen types (including collagen I and III) and has been reported, with variable expressivity, in several patients with von Willebrand Disease (Ribba et al. 2001. PubMed ID: 11583318; Flood et al. 2010. PubMed ID: 20345715; Riddell et al. 2009. PubMed ID: 19687512; Veyradier et al. 2016. PubMed ID: 26986123, see figure 6). However, several unaffected family members, who displayed only mildly altered biochemical findings, also harbored this variant, suggesting incomplete penetrance (see, for example, Riddell et al. 2009. PubMed ID: 19687512). This variant was also reported in the homozygous state in an individual with suspected Glanzmann thrombasthenia (Owaidah et al. 2019. PubMed ID: 30792900). This variant is reported in 2.1% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. A different missense change impacting the same amino acid (p.Ser1731Leu) was reported in two siblings with significantly reduced values for von Willebrand factor collagen-binding activity (Fels et al. 2022. PubMed ID: 35104900). Taken together, the VWF c.5191T>A (p.Ser1731Thr) variant is interpreted as likely pathogenic with reduced penetrance and variable expressivity. (less)
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Uncertain Significance
(Jun 23, 2022)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967578.3
First in ClinVar: Aug 26, 2019 Last updated: Apr 20, 2024 |
Comment:
The p.Ser1731Thr variant in VWF has been reported in at least 3 individuals with clinical features of Von Willebrand disease and 1 homozygous individual with … (more)
The p.Ser1731Thr variant in VWF has been reported in at least 3 individuals with clinical features of Von Willebrand disease and 1 homozygous individual with Glanzmann thrombasthenia, and segregated with disease in 2 affected relatives from 2 families. However, it was also identified in 1 individual with an alternate molecular cause of disease and 4 asymptomatic relatives (Ribba 2001 PMID: 11583318, Riddell 2009 PMID: 19687512, Veyradier 2016 PMID: 26986123, Owaidah 2019 PMID: 30792900, Al-Doory 2020). This variant has been identified in 2.1% (217/10370) of Ashkenazi Jewish chromosomes and 0.11% (136/129190) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 100420). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that the p.Ser1731Thr variant may have a partial impact to protein function (Flood 2009 PMID: 20345715, Riddell 2009 PMID: 19687512, Flood 2015 PMID: 25662333); however, these in vitro results may not be biologically relevant. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PS3_Supporting, BS1. (less)
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Likely benign
(Sep 01, 2023)
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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: SCV001249951.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
VWF: PS3:Supporting, BS1
Number of individuals with the variant: 2
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Benign
(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: SCV002513411.1
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: 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: SCV000119036.1
First in ClinVar: Feb 25, 2014 Last updated: Feb 25, 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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Von Willebrand disease type 2M: Correlation between genotype and phenotype. | Maas DPMSM | Journal of thrombosis and haemostasis : JTH | 2022 | PMID: 34758185 |
Molecular yield of targeted sequencing for Glanzmann thrombasthenia patients. | Owaidah T | NPJ genomic medicine | 2019 | PMID: 30792900 |
Interaction of von Willebrand factor domains with collagen investigated by single molecule force spectroscopy. | Posch S | The Journal of chemical physics | 2018 | PMID: 29604837 |
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 |
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 |
Crucial role for the VWF A1 domain in binding to type IV collagen. | Flood VH | Blood | 2015 | PMID: 25662333 |
New insights into genotype and phenotype of VWD. | Flood VH | Hematology. American Society of Hematology. Education Program | 2014 | PMID: 25696906 |
Analysis of the role of von Willebrand factor, platelet glycoprotein VI-, and α2β1-mediated collagen binding in thrombus formation. | Shida Y | Blood | 2014 | PMID: 25051961 |
The molecular characterization of von Willebrand disease: good in parts. | James PD | British journal of haematology | 2013 | PMID: 23406206 |
Characterizing polymorphisms and allelic diversity of von Willebrand factor gene in the 1000 Genomes. | Wang QY | Journal of thrombosis and haemostasis : JTH | 2013 | PMID: 23216583 |
The molecular genetics of von Willebrand disease. | Berber E | Turkish journal of haematology : official journal of Turkish Society of Haematology | 2012 | PMID: 24385719 |
Characterization of collagen thin films for von Willebrand factor binding and platelet adhesion. | Hansen RR | Langmuir : the ACS journal of surfaces and colloids | 2011 | PMID: 21967679 |
Absent collagen binding in a VWF A3 domain mutant: utility of the VWF:CB in diagnosis of VWD. | Flood VH | Journal of thrombosis and haemostasis : JTH | 2010 | PMID: 20345715 |
Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor. | Riddell AF | Blood | 2009 | PMID: 19687512 |
Genotype/phenotype association in von Willebrand disease: is the glass half full or empty? | Lillicrap D | Journal of thrombosis and haemostasis : JTH | 2009 | PMID: 19630771 |
Type 2M von Willebrand disease: a variant of type 2A? | Batlle J | Journal of thrombosis and haemostasis : JTH | 2008 | PMID: 18036186 |
Ser968Thr mutation within the A3 domain of von Willebrand factor (VWF) in two related patients leads to a defective binding of VWF to collagen. | Ribba AS | Thrombosis and haemostasis | 2001 | PMID: 11583318 |
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Text-mined citations for rs61750603 ...
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.