ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)
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.4883T>C (p.Ile1628Thr)
Variation ID: 284 Accession: VCV000000284.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6018535 (GRCh38) [ NCBI UCSC ] 12: 6127701 (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 Apr 4, 2013 Feb 20, 2024 Sep 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.4883T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Ile1628Thr missense NC_000012.12:g.6018535A>G NC_000012.11:g.6127701A>G NG_009072.2:g.111136T>C LRG_587:g.111136T>C LRG_587t1:c.4883T>C LRG_587p1:p.Ile1628Thr P04275:p.Ile1628Thr - Protein change
- I1628T
- Other names
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- Canonical SPDI
- NC_000012.12:6018534:A:G
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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
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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
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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
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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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Jan 21, 2019 | RCV000000308.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 29, 2023 | RCV000086808.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2019 | RCV000778377.7 | |
Pathogenic (2) |
criteria provided, single submitter
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Apr 7, 2022 | RCV002243602.2 |
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
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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
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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
(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: SCV000899346.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1:
Ethnicity/Population group: European
Observation 2:
Sex: female
Ethnicity/Population group: European
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Pathogenic
(Oct 22, 2018)
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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: SCV000914596.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The VWD c.4883T>C (p.Ile1628Thr) missense variant has been reported in at least four studies in which it is found in at least 28 individuals with … (more)
The VWD c.4883T>C (p.Ile1628Thr) missense variant has been reported in at least four studies in which it is found in at least 28 individuals with different subtypes of von Willebrand disease (VWD) (Iannuzzi et al. 1991; Melo-Nava et al. 2007; Woods et al. 2011, Ahmad et al. 2014). In one study the p.Ile1628Thr variant was found in a heterozygous state in 18 individuals affected with type 2A VWD and was shown to segregate with disease across three generations, where the authors note that all affected family members were heterozygous for the variant, while none of the unaffected members carried the variant, however only exon 28 of the VWF gene was sequenced in this study (Iannuzzi et al. 1991). In a second study, the variant was found in a heterozygous state in five individuals, all with type 2A VWD, one with mild bleeding severity, three with moderate bleeding severity and one with severe bleeding severity (Melo-Nava et al. 2007). Woods et al. (2011) reported one individual, who was heterozygous for p.Ile1628Thr variant and affected with both type 1 and type 2M VWD, who carried an additional heterozygous missense variant inherited from his mother who was affected with type VWD. The father and sister were affected with type 2M VWD and heterozygous for the p.Ile1628Thr variant. Two further individuals with type 2A VWD and heterozygous for the p.Ile1628Thr variant were also reported. Both mothers and one sister also carried the variant, but their affected status was not clear (Ahmed et al. 2014). The p.Ile1628Thr variant was absent from 334 control alleles and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database, in a region with good sequence coverage and hence is presumed to be rare. Functional studies demonstrated that the recombinant variant protein had little or no effect on the ADAMTS13-dependent proteolysis of VWF when compared to wild type (Hassenpflug et al. 2006; Zanardelli et al. 2006). Structural studies showed that the variant destabilized the native folded state of the protein and lowered the in silico tensile force which is important in the first event of the unfolding pathway (Interlandi et al. 2012). Based on the collective evidence, the p.Ile1628Thr variant is classified as 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
(Apr 07, 2022)
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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: SCV004175668.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
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Pathogenic
(Sep 29, 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: SCV004564235.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The VWF c.4883T>C; p.Ile1628Thr variant (rs61750584), also known as Ile865Thr when numbered from the mature protein, is reported in the literature in multiple individuals with … (more)
The VWF c.4883T>C; p.Ile1628Thr variant (rs61750584), also known as Ile865Thr when numbered from the mature protein, is reported in the literature in multiple individuals with Type 2A VWD and shown to co-segregate with disease (Ahmad 2014, Downes 2019, Iannuzzi 1991, Sadler 2021). This variant is also classified as pathogenic by multiple sources in the ClinVar database (Variation ID: 284). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 1628 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.703). Based on available information, this variant is considered to be pathogenic. References: Ahmad F et al. Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand disease. Haemophilia. 2014 Jul;20(4):e311-7. PMID: 24712919. Downes K et al. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. Blood. 2019 Dec 5;134(23):2082-2091. PMID: 31064749. Iannuzzi MC et al. Analysis of the relationship of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia and identification of a potential type IIA vWD mutation (IIe865 to Thr). Am J Hum Genet. 1991 Apr;48(4):757-63. PMID: 1673047. Sadler B et al. von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. Blood. 2021 Jun 10;137(23):3277-3283. PMID: 33556167. (less)
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Pathogenic
(Jan 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease, type 2a
Affected status: yes
Allele origin:
germline
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Versiti Diagnostic Laboratories, Versiti, Inc
Accession: SCV001250578.1
First in ClinVar: May 12, 2020 Last updated: May 12, 2020 |
Comment:
The missense variant VWF c.4883T>C, p.Ile1628Thr (p.I1628T) in exon 28 changes amino acid isoleucine at codon 1628 to threonine. The isoleucine at this residue is … (more)
The missense variant VWF c.4883T>C, p.Ile1628Thr (p.I1628T) in exon 28 changes amino acid isoleucine at codon 1628 to threonine. The isoleucine at this residue is highly conserved among species. This amino acid change occurs in the A2 domain, a functional domain that is cleaved by ADAMTS13 (Springer, 2014). This sequence variant has been previously reported in patients with type 2A von Willebrand disease (Iannuzzi, 1991; Hassenpflug, 2006; Ahmed, 2013) and has been observed in multiple patients with type 2A VWD in our laboratory cohort. Functional studies of the variant in mammalian cells demonstrated loss of high molecular weight multimers (Hassenpflug, 2006) due to hypersensitivity to ADAMTS13 induced increased proteolysis in plasma (Michiels, 2017). To date, this variant has not been reported in the general population (GnomAD, Exome Variant Server). In summary, the collective evidence supports VWF c.4883T>C, p.Ile1628Thr as a pathogenic variant in regards to type 2A von Willebrand disease. (less)
Number of individuals with the variant: 6
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Pathogenic
(Nov 14, 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: SCV002046420.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
Comment:
The variant has been reported in symptomatic individuals with von Willebrand Disease (VWD) Type 2A in the published literature (PMIDs: 1673047 (1991), 17681836 (2007), 22102201 … (more)
The variant has been reported in symptomatic individuals with von Willebrand Disease (VWD) Type 2A in the published literature (PMIDs: 1673047 (1991), 17681836 (2007), 22102201 (2011), 24712919 (2014), and 31064749 (2019)). Functional studies show that the variant destabilizes the native fold of the protein and is similar in expressional level with normal multimer distribution consistent with VWD 2A (PMIDs: 23110044 (2012) and 27443694 (2016).Therefore, the variant is classified as pathogenic. (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 2A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020452.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 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 ILE865THR is now designated ILE1628THR (I1628T). In affected members of a family with von Willebrand disease type 2A (see 613554), Iannuzzi et al. (1991) identified a 4883T-C transition in the VWF gene, resulting in an ile865-to-thr (I865T) substitution. Type 2A VWD is characterized by a qualitative defect in VWF, resulting in the absence of large and intermediate VWF multimers, which may be caused by increased VWF proteolysis. The I865T substitution was located immediately adjacent to 2 other previously identified mutations that also result in type 2A von Willebrand disease (R834W, 613160.0002 and V844D, 613160.0003), suggesting a clustering for these mutations in a portion of the protein critical for proteolysis. Dent et al. (1990) noted that the I865T, R834W, and V844D mutations are located within a 32-amino acid segment in the midportion of the 2,813-amino acid VWF coding sequence. Type IIA von Willebrand disease is characterized by normal or only moderately decreased levels of von Willebrand factor, the absence of large and intermediate VWF multimers, and increased VWF proteolysis with an increase in the plasma levels of the 176-kD VWF proteolytic fragment. The proteolytic cleavage site is located between tyr842 and met843. (less)
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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: SCV002515774.1
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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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: SCV002513429.1
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: SCV000119014.1
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 |
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 factor, Jedi knight of the bloodstream. | Springer TA | Blood | 2014 | PMID: 24928861 |
Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand disease. | Ahmad F | Haemophilia : the official journal of the World Federation of Hemophilia | 2014 | PMID: 24712919 |
Structural basis of type 2A von Willebrand disease investigated by molecular dynamics simulations and experiments. | Interlandi G | PloS one | 2012 | PMID: 23110044 |
Diagnosis and management of von Willebrand disease in a single institution of Argentina. | Woods AI | Seminars in thrombosis and hemostasis | 2011 | PMID: 22102201 |
The genetic basis of von Willebrand disease. | Goodeve AC | Blood reviews | 2010 | PMID: 20409624 |
Molecular study of VWF gene from Mexican Mestizo patients with von Willebrand disease, and the finding of three new mutations. | Melo-Nava BM | Blood cells, molecules & diseases | 2007 | PMID: 17681836 |
Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. | Hassenpflug WA | Blood | 2006 | PMID: 16322474 |
ADAMTS13 substrate recognition of von Willebrand factor A2 domain. | Zanardelli S | The Journal of biological chemistry | 2006 | PMID: 16221672 |
Analysis of the relationship of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia and identification of a potential type IIA vWD mutation (IIe865 to Thr). | Iannuzzi MC | American journal of human genetics | 1991 | PMID: 1673047 |
Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. | Dent JA | Proceedings of the National Academy of Sciences of the United States of America | 1990 | PMID: 2385594 |
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Text-mined citations for rs61750584 ...
HelpRecord last updated May 08, 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.