ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.2435del (p.Pro812fs)
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.2435del (p.Pro812fs)
Variation ID: 303 Accession: VCV000000303.27
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6044298 (GRCh38) [ NCBI UCSC ] 12: 6153464 (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 Mar 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.2435del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Pro812fs frameshift NM_000552.4:c.2435del NC_000012.12:g.6044303del NC_000012.11:g.6153469del NG_009072.2:g.85373del LRG_587:g.85373del LRG_587t1:c.2435del LRG_587p1:p.Pro812fs - Protein change
- P812fs
- Other names
- p.P812R fs*31
- Canonical SPDI
- NC_000012.12:6044297:GGGGGG:GGGGG
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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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- Comment on variant
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
Help
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 |
1473 | 1527 |
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) |
no assertion criteria provided
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Apr 12, 2021 | RCV000000330.14 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Mar 9, 2023 | RCV000086611.25 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000852083.9 | |
Pathogenic (2) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851752.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 9, 2024 | RCV002264635.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 8, 2022 | RCV002476902.8 |
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
(Apr 10, 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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Eurofins Ntd Llc (ga)
Accession: SCV000855028.1
First in ClinVar: Feb 25, 2014 Last updated: Feb 25, 2014 |
Number of individuals with the variant: 1
Sex: mixed
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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: SCV002546261.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Number of individuals with the variant: 2
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Pathogenic
(Mar 08, 2022)
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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: SCV002799677.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888684.3
First in ClinVar: Feb 25, 2014 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant alters the translational reading frame of the VWF mRNA and causes the premature termination of VWF protein synthesis. The frequency of this … (more)
This frameshift variant alters the translational reading frame of the VWF mRNA and causes the premature termination of VWF protein synthesis. The frequency of this variant in the general population, 0.00054 (14/26126 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been described as a common mutation in the Swedish and Finnish populations (PMIDs: 1302613 (1992), 23834637 (2013)), reported in heterozygous patients with vWD type I (PMIDs: 16985174 (2007), 17190853 (2007)), and in homozygous or compound heterozygous patients with vWD type III (PMIDs: 23834637 (2013), 29427305 (2018), 35343054 (2022)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Mar 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 1
Affected status: yes
Allele origin:
germline
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Institute of Immunology and Genetics Kaiserslautern
Accession: SCV004803198.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
ACMG Criteria: PVS1, PM2, PP5; Variant was found in heterozygous state
Clinical Features:
Abnormal thrombosis (present) , Abnormality of the vasculature (present)
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Pathogenic
(May 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002544997.11
First in ClinVar: Jul 09, 2022 Last updated: May 12, 2024 |
Comment:
VWF: PVS1, PM2
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: SCV000899623.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
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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Abnormal bleeding
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899624.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: male
Ethnicity/Population group: European
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Pathogenic
(Dec 20, 1993)
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no assertion criteria provided
Method: literature only
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VON WILLEBRAND DISEASE, TYPE 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020474.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
Among 24 patients with von Willebrand disease type 3 (277480), Zhang et al. (1992) found that 24 of the 48 chromosomes harbored a 1-bp deletion … (more)
Among 24 patients with von Willebrand disease type 3 (277480), Zhang et al. (1992) found that 24 of the 48 chromosomes harbored a 1-bp deletion in a stretch of 6 cytosines at position 2679-2684 in exon 18 of the VWF gene. Nine patients were homozygous and 6 were heterozygous for the mutation. The deletion interrupted the reading frame and resulted in a translational stop codon at position V842 in the amino acid sequence. Translation of the mutant mRNA would yield only a severely truncated mature VWF (48 of 2,050 amino acids) after removal of the propeptide. Zhang et al. (1993) demonstrated that deletion of 1 cytosine in exon 18 was the mutation in the Aland family (family S) in which the disease was first reported by von Willebrand (1926). They reported studies of descendants of the original family; only heterozygotes were found surviving. The proposita was a 5-year-old girl, who later bled to death during her fourth menstrual period. She had a normal coagulation time, but the bleeding time was prolonged, despite a normal platelet count. All but 1 of her 11 sibs had bleeding symptoms, as did both of her parents, who were third cousins, and many members of her family on both sides. Four of the proband's sisters had died of uncontrolled bleeding in early childhood; 3 died from gastrointestinal bleeding and 1 from bleeding after she bit her tongue in a fall. The predominant symptoms were bleeding from mucous membranes, such as from the nose, the gingivae after tooth extractions, the uterus, and the gastrointestinal tract. In contrast to hemophilia, hemarthroses seemed to be rare. All 5 of the girls who died from uncontrolled bleeding were probably homozygous for the deletion. Mertes et al. (1993) found that the single cytosine deletion in exon 18 observed in half the alleles of 24 Swedish VWD type 3 patients (Zhang et al., 1992) occurred uncommonly in German patients with type 3 VWD; only 1 out of 24 alleles carried the delta-C mutation. A founder effect might explain the higher frequency in Sweden. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978298.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Apr 12, 2021)
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no assertion criteria provided
Method: clinical testing
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von Willebrand disease type 3
Affected status: yes
Allele origin:
germline
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Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Study: Type 3 Von Willebrand International Registries Inhibitor Prospective Study (3WINTERS-IPS)
Accession: SCV001572662.1 First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001980128.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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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: SCV002507238.2
First in ClinVar: May 16, 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: SCV000118815.1
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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Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program. | Christopherson PA | Journal of thrombosis and haemostasis : JTH | 2022 | PMID: 35343054 |
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
Comprehensive re-evaluation of historical von Willebrand disease diagnosis in association with whole blood platelet aggregation and function. | Nummi V | International journal of laboratory hematology | 2018 | PMID: 29427305 |
von Willebrand Disease. | Adam MP | - | 2017 | PMID: 20301765 |
Phenotypic and genotypic characterization of 10 Finnish patients with von Willebrand disease type 3: discovery of two main mutations. | Jokela V | Haemophilia : the official journal of the World Federation of Hemophilia | 2013 | PMID: 23834637 |
Critical von Willebrand factor A1 domain residues influence type VI collagen binding. | Flood VH | Journal of thrombosis and haemostasis : JTH | 2012 | PMID: 22507569 |
Common large partial VWF gene deletion does not cause alloantibody formation in the Hungarian type 3 von Willebrand disease population. | Mohl A | Journal of thrombosis and haemostasis : JTH | 2011 | PMID: 21362127 |
Polymorphic variation within the VWF gene contributes to the failure to detect mutations in patients historically diagnosed with type 1 von Willebrand disease from the MCMDM-1VWD cohort. | Hampshire DJ | Haematologica | 2010 | PMID: 20851871 |
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 |
Genetic heterogeneity of severe von Willebrand disease type III in the German population. | Schneppenheim R | Human genetics | 1994 | PMID: 7989040 |
Mutations of von Willebrand factor gene in families with von Willebrand disease in the Aland Islands. | Zhang ZP | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8367445 |
Delta C in exon 18 of the von Willebrand gene is uncommon in German vWD type III patients. | Mertes G | Thrombosis and haemostasis | 1993 | PMID: 8165603 |
A single cytosine deletion in exon 18 of the von Willebrand factor gene is the most common mutation in Swedish vWD type III patients. | Zhang ZP | Human molecular genetics | 1992 | PMID: 1302613 |
Identification of a new nonsense mutation in the von Willebrand factor gene in patients with von Willebrand disease type III. | Zhang ZP | Human molecular genetics | 1992 | PMID: 1301136 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VWF | - | - | - | - |
von Willebrand, E. A. Hereditar pseudohemofili. Finska Lakar. Hand. 68: 87-112, 1926. | - | - | - | - |
www.varsome.com | - | - | - | - |
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Text-mined citations for rs62643632 ...
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.
NCBI staff reviewed the sequence information reported in PubMed 1302613 Fig. 1 to determine the location of this allele on the current reference sequence.