ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.7988G>C (p.Arg2663Pro)
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(1); Uncertain significance(7); 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.7988G>C (p.Arg2663Pro)
Variation ID: 372760 Accession: VCV000372760.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 5952518 (GRCh38) [ NCBI UCSC ] 12: 6061684 (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 Jan 9, 2017 May 12, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.7988G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Arg2663Pro missense NC_000012.12:g.5952518C>G NC_000012.11:g.6061684C>G NG_009072.2:g.177153G>C LRG_587:g.177153G>C LRG_587t1:c.7988G>C LRG_587p1:p.Arg2663Pro - Protein change
- R2663P
- Other names
- -
- Canonical SPDI
- NC_000012.12:5952517:C: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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0.00100 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00100
Trans-Omics for Precision Medicine (TOPMed) 0.00108
1000 Genomes Project 30x 0.00109
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00131
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
Help
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 |
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
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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Uncertain significance (1) |
criteria provided, single submitter
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May 4, 2022 | RCV000413262.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851890.1 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 1, 2024 | RCV000986090.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 4, 2018 | RCV000778372.4 | |
Uncertain significance (1) |
no assertion criteria provided
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May 1, 2020 | RCV001270575.1 | |
Uncertain significance (2) |
criteria provided, single submitter
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- | RCV002280878.3 |
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 23, 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: SCV000491223.2
First in ClinVar: Jan 09, 2017 Last updated: Jul 08, 2023 |
Comment:
Observed in individuals with von Willebrand disease or other unspecified bleeding disorders (Goodeve et al., 2007; Downes et al., 2019; Almazni et al., 2020; Vangenechten … (more)
Observed in individuals with von Willebrand disease or other unspecified bleeding disorders (Goodeve et al., 2007; Downes et al., 2019; Almazni et al., 2020; Vangenechten et al., 2022); Published functional studies suggest this variant does not impair glycoprotein IIb/llla binding (Konig et al. 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23648131, 27320760, 34426522, 31064749, 32935436, 31035301, 31968368, 31352677, 16985174, 34708896, 36299619) (less)
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Likely pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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Abnormality of coagulation
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899939.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: female
Ethnicity/Population group: European
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Uncertain significance
(Dec 04, 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: SCV000914591.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The VWF c.7988G>C (p.Arg2663Pro) missense variant has been reported in one study in which it is found in one individual with von Willebrand disease in … (more)
The VWF c.7988G>C (p.Arg2663Pro) missense variant has been reported in one study in which it is found in one individual with von Willebrand disease in a heterozygous state (Goodeve et al. 2008). The p.Arg2663Pro variant is absent from 100 controls, and is reported at a frequency of 0.002277 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited evidence, the p.Arg2663Pro variant is classified as a variant of unknown significance but suspicious for pathogenicity 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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Uncertain significance
(May 04, 2022)
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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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Mendelics
Accession: SCV002516161.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Uncertain significance
(-)
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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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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002569254.1
First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022
Comment:
Submitted to GoldVariant by Kathleen Freson, Center for Molecular and Vascular Biology, Leuven, Belgium
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Clinical Features:
Bleeding (present) , Low von Willebrand antigen (present)
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Uncertain significance
(Jun 26, 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: SCV001134924.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with Type 1 von Willebrand disease (VWD) (PMID: 16985174 (2007), 36299619 (2022)), deep vein … (more)
In the published literature, this variant has been reported in individuals with Type 1 von Willebrand disease (VWD) (PMID: 16985174 (2007), 36299619 (2022)), deep vein thrombosis (PMID: 23648131 (2013)), thrombocytopenia-absent radius (TAR) syndrome (PMID: 27320760 (2016)), bleeding/platelet disorders (PMID: 31064749 (2019), 32935436 (2020)), and hemophilia (PMID: 34708896 (2021)). The frequency of this variant in the general population, 0.0049 (57/11588 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Mar 06, 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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Revvity Omics, Revvity
Accession: SCV004237530.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Uncertain significance
(Nov 14, 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: SCV004564865.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The VWF c.7988G>C; p.Arg2663Pro variant (rs149834874) is reported in the literature in the compound heterozygous state in an individual affected with type 1 von Willebrand … (more)
The VWF c.7988G>C; p.Arg2663Pro variant (rs149834874) is reported in the literature in the compound heterozygous state in an individual affected with type 1 von Willebrand disease (Goodeve 2007). This variant is also reported in individuals with other bleeding disorders, either with alternate molecular explanation for disease or without clear disease association (Borras 2022, Connaughton 2023, Downes 2019, Nicchia 2016). This variant is also reported in ClinVar (Variation ID: 372760), and is found in the general population with an overall allele frequency of 0.14% (404/282,640 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.258). Due to limited clinical and functional data, the significance of this variant is uncertain at this time. References: Borras N et al. Molecular study of a large cohort of 109 haemophilia patients from Cuba using a gene panel with next generation sequencing-based technology. Haemophilia. 2022 Jan;28(1):125-137. PMID: 34708896. Connaughton DM et al. Genotypic analysis of a large cohort of patients with suspected atypical hemolytic uremic syndrome. J Mol Med (Berl). 2023 Aug;101(8):1029-1040. PMID: 37466676. 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. Goodeve A et al. 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). Blood. 2007 Jan 1;109(1):112-21. PMID: 16985174. Nicchia E et al. Molecular diagnosis of thrombocytopenia-absent radius syndrome using next-generation sequencing. Int J Lab Hematol. 2016 Aug;38(4):412-8. PMID: 27320760. (less)
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Likely benign
(Jan 01, 2024)
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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: SCV001148561.14
First in ClinVar: Feb 03, 2020 Last updated: May 12, 2024 |
Comment:
VWF: BP4
Number of individuals with the variant: 1
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Uncertain significance
(May 01, 2020)
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no assertion criteria provided
Method: research
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Thrombocytopenia
Abnormal bleeding
Affected status: yes
Allele origin:
germline
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Birmingham Platelet Group; University of Birmingham
Accession: SCV001450874.1
First in ClinVar: Dec 19, 2020 Last updated: Dec 19, 2020 |
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Uncertain significance
(Oct 30, 2023)
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no assertion criteria provided
Method: clinical testing
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von Willebrand disease type 1
Affected status: yes
Allele origin:
germline
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Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004099355.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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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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Analysis of von Willebrand Disease in the "Heart of Europe". | Vangenechten I | TH open : companion journal to thrombosis and haemostasis | 2022 | PMID: 36299619 |
Molecular study of a large cohort of 109 haemophilia patients from Cuba using a gene panel with next generation sequencing-based technology. | Borràs N | Haemophilia : the official journal of the World Federation of Hemophilia | 2022 | PMID: 34708896 |
A comprehensive bioinformatic analysis of 126 patients with an inherited platelet disorder to identify both sequence and copy number genetic variants. | Almazni I | Human mutation | 2020 | PMID: 32935436 |
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
Molecular diagnosis of thrombocytopenia-absent radius syndrome using next-generation sequencing. | Nicchia E | International journal of laboratory hematology | 2016 | PMID: 27320760 |
Next-generation sequencing study finds an excess of rare, coding single-nucleotide variants of ADAMTS13 in patients with deep vein thrombosis. | Lotta LA | Journal of thrombosis and haemostasis : JTH | 2013 | PMID: 23648131 |
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 |
Text-mined citations for rs149834874 ...
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.