ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.3946G>A (p.Val1316Met)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000552.5(VWF):c.3946G>A (p.Val1316Met)
Variation ID: 290 Accession: VCV000000290.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6019472 (GRCh38) [ NCBI UCSC ] 12: 6128638 (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 May 5, 2013 May 12, 2024 Nov 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.3946G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Val1316Met missense NC_000012.12:g.6019472C>T NC_000012.11:g.6128638C>T NG_009072.2:g.110199G>A LRG_587:g.110199G>A LRG_587t1:c.3946G>A LRG_587p1:p.Val1316Met P04275:p.Val1316Met - Protein change
- V1316M
- Other names
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- Canonical SPDI
- NC_000012.12:6019471:C: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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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 (2) |
criteria provided, single submitter
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Sep 20, 2019 | RCV000000314.5 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2020 | RCV000086715.20 | |
Pathogenic (1) |
criteria provided, single submitter
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May 9, 2019 | RCV000507168.10 | |
Pathogenic (4) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000678767.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 9, 2023 | RCV000851771.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 6, 2021 | RCV002476901.2 |
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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Pathogenic
(May 09, 2019)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605571.2
First in ClinVar: Sep 30, 2017 Last updated: Feb 09, 2020 |
Comment:
The VWF c.3946G>A; p.Val1316Met variant (rs61749397), also known in traditional nomenclature as p.Val553Met, is described in the literature in individuals and families with von Willebrand … (more)
The VWF c.3946G>A; p.Val1316Met variant (rs61749397), also known in traditional nomenclature as p.Val553Met, is described in the literature in individuals and families with von Willebrand disease type 2B (Casana 1998, Federici 2009, Goodeve 2010, Jackson 2009, Randi 1991). This variant been described in at least one family to segregate with disease with autosomal dominant inheritance (Jackson 2009) and has also been found to occur de novo (Randi 1990). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by several laboratories in ClinVar (Variation ID: 290). The valine at codon 1316 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Further, a mouse model expressing the p.Val1316Met variant exhibits similar physiological symptoms as human patients with this variant, including increased bleeding, reduced platelet aggregation, and macrothrombocytopenia (Adam 2016,Kauskot 2016). Based on available information, the p.Val1316Met variant is considered to be pathogenic. References: Adam F et al. A genetically-engineered von Willebrand disease type 2B mouse model displays defects in hemostasis and inflammation. Sci Rep. 2016 May 23;6:26306. Casana P et al. Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants. Am J Hematol. 1998 Sep;59(1):57-63. 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. Goodeve AC. The genetic basis of von Willebrand disease. Blood Rev. 2010 May;24(3):123-34 Jackson SC et al. The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation. Blood. 2009 Apr 2;113(14):3348-51. Kauskot A et al. LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B. JCI Insight. 2016 Oct 6;1(16):e88643. Randi AM et al. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. J Clin Invest. 1991 Apr;87(4):1220-6. (less)
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Pathogenic
(Sep 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease, type 2b
Affected status: yes
Allele origin:
germline
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Versiti Diagnostic Laboratories, Versiti, Inc
Accession: SCV001250573.1
First in ClinVar: May 12, 2020 Last updated: May 12, 2020 |
Comment:
The missense variant VWF c.3946G>A, p.Val1316Met (p.V1316M; mature protein p.V553M) in exon 28 changes amino acid valine at codon 1316 to methionine. The valine at … (more)
The missense variant VWF c.3946G>A, p.Val1316Met (p.V1316M; mature protein p.V553M) in exon 28 changes amino acid valine at codon 1316 to methionine. The valine at this residue is highly conserved among species. This amino acid change occurs in the A1 domain, a functional domain that binds GPIba (Springer, 2014). Pathogenic variants in VWF are associated with autosomal dominant or autosomal recessive von Willebrand disease (VWD), characterized by quantitative or qualitative deficiencies in von Willebrand factor and resulting in prolonged bleeding. This sequence variant has been previously reported in patients with type 2B VWD. Patients with this variant have a unique phenotype of severe thrombocytopenia, bleeding, giant platelets, and spontaneous platelet aggregation in vitro (Jackson, 2009; Poon, 2010; Espitia, 2017; Rotz, 2017). To date, this variant has not been reported in the general population (GnomAD, Exome Variant Server, ExAC, Variation Viewer). Functional studies of the p.V1316M variant in COS-7 cells mimic the patient laboratory phenotype: binding is significantly increased in the absence of agonist, in the presence of ristocetin, or in the presence of low concentrations of botrocetin, and platelet aggregation is increased by SIPA (Ajzenberg, 2000). In summary, the collective evidence supports VWF c.3946G>A, p.Val1316Met as a pathogenic variant for type 2B VWD. (less)
Number of individuals with the variant: 14
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Pathogenic
(Apr 27, 2018)
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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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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888689.2
First in ClinVar: Feb 21, 2014 Last updated: Jan 01, 2022 |
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Pathogenic
(Aug 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 1
von Willebrand disease type 3 von Willebrand disease type 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002788866.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 01, 2020)
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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: SCV001500986.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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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: SCV000899336.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1:
Sex: male
Ethnicity/Population group: European
Observation 2:
Sex: female
Ethnicity/Population group: European
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Pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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von Willebrand disease type 2
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899706.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: female
Ethnicity/Population group: East-Asian
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Pathogenic
(Nov 09, 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: SCV004175325.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The VWF c.3946G>A variant is classified as Pathogenic (PS3_Strong, PS4_Strong, PM2_Moderate, PP3_Supporting) The VWF c.3946G>A variant is a single nucleotide change in exon 28/52 of … (more)
The VWF c.3946G>A variant is classified as Pathogenic (PS3_Strong, PS4_Strong, PM2_Moderate, PP3_Supporting) The VWF c.3946G>A variant is a single nucleotide change in exon 28/52 of the VWF gene, which is predicted to change the amino acid valine at position 1316 in the protein to methionine. The variant has been reported in dbSNP (rs61749397) and in the HGMD database: CM910400. Well-established functional studies in mouse models have shown a deleterious effect of this variant resulting in diminished platelet aggregation (PMID: 24270421 and PMID: 20317142) (PS3_Strong). The variant has been commonly reported in probands with a clinical presentation of von Willebrand Disease type 2B (PS4_Strong). This variant is absent from population databases (PM2_Moderate). Computational predictions support a deleterious effect on the gene or gene product (REVEL >0.7.) (PP3_Supporting). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 290). (less)
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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: SCV000020458.2
First in ClinVar: Apr 04, 2013 Last updated: May 05, 2013 |
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 VAL553MET is now designated VAL1316MET (V1316M). In a patient with VWD type 2B (see 613554), Randi et al. (1991) identified a heterozygous 4196G-A transition in exon 28 of the VWF gene, resulting in a val553-to-met (V553M) substitution in the domain that interacts with platelet glycoprotein GP1BA (606672). Patient plasma showed a decrease in large VWF multimers due to spontaneous binding of VWF to platelets and subsequent clearance from the circulation. Murray et al. (1992) also observed this mutation in multiple members of a family with type 2B von Willebrand disease. They showed by VWF polymorphism analysis that the mutation originated in a VWF gene transmitted from a phenotypically normal grandfather. Analysis of the sperm from this individual showed that approximately 5% of the germline contained the mutant sequence. Jackson et al. (2009) identified a heterozygous V1316M substitution in affected members of a large French Canadian family with VWD type 2B that was described by Milton et al. (1984) as having the 'Montreal platelet syndrome.' Affected individuals had lifelong bruising; some patients had severe postoperative bleeding, postpartum hemorrhage, and gastrointestinal bleeding. A significant proportion of platelets occurred in microaggregates typically containing 2 to 6 platelets, and the aggregation could be increased by stirring. Affected family members had macrothrombocytopenia, borderline to normal VWF antigen, low ristocetin cofactor activity, and normal factor VIII coagulant activity, all consistent with VWD type 2B. (less)
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Pathogenic
(Jan 23, 2006)
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no assertion criteria provided
Method: clinical testing
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von Willebrand disorder
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804946.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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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: SCV002513391.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Hereditary von Willebrand disease
Affected status: yes
Allele origin:
unknown
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002515781.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Comment:
Submitted to GoldVariant by Dr Karyn Mégy from NIHR Bioresource - Cambridge University, UK
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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: SCV002507248.2
First in ClinVar: May 11, 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: SCV000118920.1
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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Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
Type 2B von Willebrand Disease: An Unusual Cause of Severe Neonatal Thrombocytopenia. | Rotz SJ | Journal of pediatric hematology/oncology | 2017 | PMID: 28060120 |
Use of a thrombopoietin receptor agonist in von Willebrand disease type 2B (p.V1316M) with severe thrombocytopenia and intracranial hemorrhage. | Espitia O | Platelets | 2017 | PMID: 27885890 |
von Willebrand Disease. | Adam MP | - | 2017 | PMID: 20301765 |
von Willebrand factor, Jedi knight of the bloodstream. | Springer TA | Blood | 2014 | PMID: 24928861 |
2B or not to be--the 45-year saga of the Montreal Platelet Syndrome. | Poon MC | Thrombosis and haemostasis | 2010 | PMID: 20838735 |
The genetic basis of von Willebrand disease. | Goodeve AC | Blood reviews | 2010 | PMID: 20409624 |
The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation. | Jackson SC | Blood | 2009 | PMID: 19060241 |
Effect of recombinant von Willebrand factor reproducing type 2B or type 2M mutations on shear-induced platelet aggregation. | Ajzenberg N | Blood | 2000 | PMID: 10845912 |
Germ-line mosaicism for a valine-to-methionine substitution at residue 553 in the glycoprotein Ib-binding domain of von Willebrand factor, causing type IIB von Willebrand disease. | Murray EW | American journal of human genetics | 1992 | PMID: 1729889 |
Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. | Randi AM | The Journal of clinical investigation | 1991 | PMID: 2010538 |
Spontaneous platelet aggregation in a hereditary giant platelet syndrome (MPS). | Milton JG | The American journal of pathology | 1984 | PMID: 6696046 |
The Edinburgh Letter. | Gibson G | Canadian Medical Association journal | 1928 | PMID: 20317142 |
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Text-mined citations for rs61749397 ...
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.