ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.7940C>T (p.Thr2647Met)
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.
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.7940C>T (p.Thr2647Met)
Variation ID: 100487 Accession: VCV000100487.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 5953542 (GRCh38) [ NCBI UCSC ] 12: 6062708 (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 Feb 20, 2024 Jun 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.7940C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Thr2647Met missense NC_000012.12:g.5953542G>A NC_000012.11:g.6062708G>A NG_009072.2:g.176129C>T LRG_587:g.176129C>T LRG_587t1:c.7940C>T LRG_587p1:p.Thr2647Met - Protein change
- T2647M
- Other names
- -
- Canonical SPDI
- NC_000012.12:5953541:G:A
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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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0.00140 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00161
Trans-Omics for Precision Medicine (TOPMed) 0.00193
Exome Aggregation Consortium (ExAC) 0.00274
The Genome Aggregation Database (gnomAD), exomes 0.00351
The Genome Aggregation Database (gnomAD) 0.00352
1000 Genomes Project 30x 0.00109
1000 Genomes Project 0.00140
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 |
1492 | 1546 |
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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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Jun 28, 2023 | RCV000086901.9 | |
Uncertain significance (2) |
criteria provided, single submitter
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- | RCV002225290.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV002225291.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765101.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 10, 2019 | RCV000851886.2 |
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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Uncertain significance
(Jun 15, 2017)
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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: SCV000589617.2
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Comment:
The T2647M variant in the VWF gene has been reported previously in individuals with VWF type 1 and in healthy controls (Bellissimo et al., 2012; … (more)
The T2647M variant in the VWF gene has been reported previously in individuals with VWF type 1 and in healthy controls (Bellissimo et al., 2012; James et al., 2007a; James et al., 2007b). The T2647M variant is observed in 112/6614 (1.7%) alleles from individuals of Finnish European background including multiple unrelated homozygous individuals in the ExAC dataset, which is greater than expected for this disorder (Lek et al., 2016). This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, the T2647M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.We interpret T2647M as a variant of uncertain significance. (less)
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Uncertain significance
(Oct 31, 2018)
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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: SCV000896321.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(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: SCV000899935.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: female
Ethnicity/Population group: European
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Uncertain significance
(-)
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criteria provided, single submitter
Method: research
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von Willebrand disease type 1
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: SCV002505351.1
First in ClinVar: Apr 29, 2022 Last updated: Apr 29, 2022
Comment:
Goldvariant submitter:Karyn Mégy, NIHR Bioresource - Cambridge University, UK
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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 3
Affected status: yes
Allele origin:
paternal
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002505352.1
First in ClinVar: Apr 29, 2022 Last updated: Apr 29, 2022
Comment:
Goldvariant submitter:Kathleen Freson, Center for Molecular and Vascular Biology, Leuven, Belgium
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Uncertain significance
(Sep 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary von Willebrand disease
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761402.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Uncertain significance
(Jan 21, 2022)
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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: SCV001134923.5
First in ClinVar: Jan 05, 2020 Last updated: Dec 31, 2022 |
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Likely benign
(Jun 28, 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: SCV004564681.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
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Likely benign
(-)
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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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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979476.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Likely benign
(-)
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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: SCV001980198.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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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: SCV004099481.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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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: SCV000119107.1
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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GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis. | Megy K | Journal of thrombosis and haemostasis : JTH | 2021 | PMID: 34355501 |
von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. | Sadler B | Blood | 2021 | PMID: 33556167 |
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
Targeted re-sequencing of F8, F9 and VWF: Characterization of Ion Torrent data and clinical implications for mutation screening. | Manderstedt E | PloS one | 2019 | PMID: 31026269 |
Characterizing polymorphisms and allelic diversity of von Willebrand factor gene in the 1000 Genomes. | Wang QY | Journal of thrombosis and haemostasis : JTH | 2013 | PMID: 23216583 |
VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. | Bellissimo DB | Blood | 2012 | PMID: 22197721 |
Dominant von Willebrand disease type 2M and 2U are variable expressions of one distinct disease entity caused by loss-of-function mutations in the A1 domain of the von Willebrand factor gene. | Gadisseur A | Acta haematologica | 2009 | PMID: 19506361 |
The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. | James PD | Blood | 2007 | PMID: 17190853 |
Text-mined citations for rs61751302 ...
HelpRecord last updated Jun 23, 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.