ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.3437A>G (p.Tyr1146Cys)
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.3437A>G (p.Tyr1146Cys)
Variation ID: 31009 Accession: VCV000031009.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6022841 (GRCh38) [ NCBI UCSC ] 12: 6132007 (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 Jul 18, 2022 May 25, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.3437A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Tyr1146Cys missense NC_000012.12:g.6022841T>C NC_000012.11:g.6132007T>C NG_009072.2:g.106830A>G LRG_587:g.106830A>G LRG_587t1:c.3437A>G LRG_587p1:p.Tyr1146Cys - Protein change
- Y1146C
- Other names
- p.Y1146C
- Canonical SPDI
- NC_000012.12:6022840:T:C
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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
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
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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 |
1438 | 1492 |
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 (3) |
criteria provided, single submitter
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Dec 10, 2020 | RCV000024001.6 | |
not provided (1) |
no classification provided
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- | RCV000086656.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 25, 2022 | RCV000851956.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 25, 2020 | RCV001800314.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 10, 2020 | RCV002264640.1 |
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
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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: SCV000899379.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: female
Ethnicity/Population group: East-Asian
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Pathogenic
(Sep 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046240.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
Comment:
The variant has been reported as a relatively common variant in Type 2A vWD and some Type 1 vWD patients the published literature (PMID: 16985174 … (more)
The variant has been reported as a relatively common variant in Type 2A vWD and some Type 1 vWD patients the published literature (PMID: 16985174 (2007), 17190853 (2007), 20351307 (2010), 22871923 (2012), 26986123 (2016), 26988807 (2016), 29388750 (2018), 29742318 (2018), 31249928 (2018), 31064749 (2019)). Functional studies showed that this variant caused defective intracellular packaging, reduced VWF secretion, and a FVIII binding defect as well as loss of large multimers and decreased proteolysis (PMID: 18230755 (2008), 20351307 (2010), 24598842 (2014), 27533707 (2016)). Therefore, the variant is classified as pathogenic. (less)
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Pathogenic
(Dec 10, 2020)
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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: SCV002546275.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Number of individuals with the variant: 2
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Pathogenic
(Dec 10, 2020)
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criteria provided, single submitter
Method: research
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von Willebrand disease type 2
Affected status: yes
Allele origin:
germline
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Laboratory of Hematology, Radboud University Medical Center
Study: WIN study
Accession: SCV002546277.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Number of individuals with the variant: 1
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Pathogenic
(May 25, 2022)
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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: SCV002548089.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: VWF c.3437A>G (p.Tyr1146Cys) results in a non-conservative amino acid change located in the Trypsin Inhibitor-like, cysteine rich domain (IPR002919) of the encoded protein … (more)
Variant summary: VWF c.3437A>G (p.Tyr1146Cys) results in a non-conservative amino acid change located in the Trypsin Inhibitor-like, cysteine rich domain (IPR002919) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 54460 control chromosomes. c.3437A>G has been reported in the literature in multiple individuals affected with Type I and Type II Von Willebrand Disease (example, Goodeve_2007, Castaman_2008, James_2007, Schneppenheim_2010, Manderstedt_2018, Fidalgo_2016). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in inhibition of normal processing, string formation and platelet binding (Brehm_2014), defective intracellular packaging and markedly reduced VWF secretion. Loss of HMW Multimers. Demonstrated a novel FVIII binding defect (White-Adams_2016) and reduced expression (Schneppenheim_2010). One clinical diagnostic laboratory and the NIHR Bioresource Rare Diseases have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 10, 2010)
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no assertion criteria provided
Method: literature only
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VON WILLEBRAND DISEASE, TYPE 2A/IIE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045292.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In 12 (32%) of 38 probands with von Willebrand disease type 2A/IIE (see 613554), Schneppenheim et al. (2010) identified a heterozygous 3437A-C transversion in exon … (more)
In 12 (32%) of 38 probands with von Willebrand disease type 2A/IIE (see 613554), Schneppenheim et al. (2010) identified a heterozygous 3437A-C transversion in exon 26 of the VWF gene, resulting in a tyr1146-to-cys (Y1146C) substitution in the D3 domain. Plasma from patients showed complete absence of large VWF multimers, and in vitro expression studies indicated that the Y1146C-mutant protein caused a severe reduction in or lack of high molecular weight monomers. and decreased secreted VWF antigen levels. However, clinical symptoms were heterogeneous among carriers, ranging from mild to severe bleeding. Schneppenheim et al. (2010) suggested several mechanisms acting in concert, including decreased secretion of VWF, the change affecting a cysteine residue which may impact multimerization, and decreased half-life of the mutant protein. Altered ADAMTS13-mediated proteolysis did not appear to be a primary factor. (less)
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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: SCV002513370.1
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: SCV000118860.1
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 |
Genetic Variation in the von Willebrand Factor Gene in Swedish von Willebrand Disease Patients. | Manderstedt E | TH open : companion journal to thrombosis and haemostasis | 2018 | PMID: 31249928 |
A comparative analysis of different automated von Willebrand factor glycoprotein Ib-binding activity assays in well typed von Willebrand disease patients. | Vangenechten I | Journal of thrombosis and haemostasis : JTH | 2018 | PMID: 29742318 |
High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB). | Gebhart J | Haemophilia : the official journal of the World Federation of Hemophilia | 2018 | PMID: 29388750 |
Mutations in the D'D3 region of VWF traditionally associated with type 1 VWD lead to quantitative and qualitative deficiencies of VWF. | White-Adams TC | Thrombosis research | 2016 | PMID: 27533707 |
Genotype-phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS. | Fidalgo T | Thrombosis and haemostasis | 2016 | PMID: 26988807 |
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 |
von Willebrand disease type 2A phenotypes IIC, IID and IIE: A day in the life of shear-stressed mutant von Willebrand factor. | Brehm MA | Thrombosis and haemostasis | 2014 | PMID: 24598842 |
Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients. | Yadegari H | Thrombosis and haemostasis | 2012 | PMID: 22871923 |
Variation in the VWF gene in Swedish patients with type 1 von Willebrand Disease. | Johansson AM | Annals of human genetics | 2011 | PMID: 21534937 |
A cluster of mutations in the D3 domain of von Willebrand factor correlates with a distinct subgroup of von Willebrand disease: type 2A/IIE. | Schneppenheim R | Blood | 2010 | PMID: 20351307 |
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 |
Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. | Castaman G | Blood | 2008 | PMID: 18230755 |
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 |
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Text-mined citations for rs267607326 ...
HelpRecord last updated Mar 17, 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.