Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35505650, 31050121, 25525159, 1301136, 31589614, 29423401, 23834637, 9845532, 24712919, 18485763, 20147343)
ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.4975C>T (p.Arg1659Ter)
Germline
Classification
Help
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.
(10)
Help
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.
Pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000552.5(VWF):c.4975C>T (p.Arg1659Ter)
Variation ID: 297 Accession: VCV000000297.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12p13.31 12: 6018443 (GRCh38) [ NCBI UCSC ] 12: 6127609 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 8, 2024 Oct 2, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000552.5:c.4975C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Arg1659Ter nonsense NC_000012.12:g.6018443G>A NC_000012.11:g.6127609G>A NG_009072.2:g.111228C>T LRG_587:g.111228C>T LRG_587t1:c.4975C>T LRG_587p1:p.Arg1659Ter - Protein change
- R1659*
- Other names
- -
- Canonical SPDI
- NC_000012.12:6018442:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| VWF | - | - |
GRCh38 GRCh37 |
1566 | 1620 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
- | RCV000000323.15 | |
| Pathogenic (2) |
no assertion criteria provided
|
Nov 1, 2020 | RCV000000322.13 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 2, 2022 | RCV000086820.12 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jul 19, 2022 | RCV002227437.11 | |
|
VWF-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Apr 17, 2024 | RCV004739271.1 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
von Willebrand disease type 1
Affected status: yes
Allele origin:
unknown
|
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002500927.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Comment:
GoldVariant submitter: Dr Karyn Mégy NIHR Bioresource - Cambridge University, UK
|
Observation 1: Observation 2: Observation 3: |
|
|
Pathogenic
(Oct 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003852846.1
First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35505650, 31050121, 25525159, 1301136, 31589614, 29423401, 23834637, 9845532, 24712919, 18485763, 20147343) (less)
|
|
|
Pathogenic
(Nov 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470131.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
This nonsense variant causes the premature termination of VWF protein synthesis. In addition, it has been reported in individuals affected with VWD Type 3 in … (more)
This nonsense variant causes the premature termination of VWF protein synthesis. In addition, it has been reported in individuals affected with VWD Type 3 in the published literature (PMID: 20147343 (2010), 24712919 (2014), 18485763 (2008), 23834637 (2013), 28971901 (2017), 24675615 (2014)). Therefore, the variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
von Willebrand disorder
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002570649.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: VWF c.4975C>T (p.Arg1659X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: VWF c.4975C>T (p.Arg1659X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.6e-05 in 250392 control chromosomes. This frequency does not allow conclusions about variant significance. c.4975C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Von Willebrand Disease type 3 (example, Mohl_2011, Lapi_2022, Zhang_1992, Ahmad_2014). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 01, 1992)
|
no assertion criteria provided
Method: literature only
|
VON WILLEBRAND DISEASE, TYPE 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020466.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 22, 2014 |
Comment on evidence:
In a patient with von Willebrand disease type 3 (277480), Zhang et al. (1992) identified a homozygous C-to-T transition in exon 28 of the VWF … (more)
In a patient with von Willebrand disease type 3 (277480), Zhang et al. (1992) identified a homozygous C-to-T transition in exon 28 of the VWF gene, resulting in an arg1659-to-ter (R1659X) substitution. Both parents carried the heterozygous mutation; the clinical features of the family were not reported. Zhang et al. (1992) identified the R1659X mutation in affected members of 3 families from western Finland with VWD type 3. Severely affected individuals were either homozygous or presumed to be compound heterozygous with another pathogenic mutation. In 1 family, heterozygous mutation carriers had a less severe phenotype, consistent with type 1 VWD (193400). (less)
|
|
|
Pathogenic
(Dec 01, 1992)
|
no assertion criteria provided
Method: literature only
|
VON WILLEBRAND DISEASE, TYPE 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020467.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 22, 2014 |
Comment on evidence:
In a patient with von Willebrand disease type 3 (277480), Zhang et al. (1992) identified a homozygous C-to-T transition in exon 28 of the VWF … (more)
In a patient with von Willebrand disease type 3 (277480), Zhang et al. (1992) identified a homozygous C-to-T transition in exon 28 of the VWF gene, resulting in an arg1659-to-ter (R1659X) substitution. Both parents carried the heterozygous mutation; the clinical features of the family were not reported. Zhang et al. (1992) identified the R1659X mutation in affected members of 3 families from western Finland with VWD type 3. Severely affected individuals were either homozygous or presumed to be compound heterozygous with another pathogenic mutation. In 1 family, heterozygous mutation carriers had a less severe phenotype, consistent with type 1 VWD (193400). (less)
|
|
|
Pathogenic
(Nov 01, 2020)
|
no assertion criteria provided
Method: clinical testing
|
von Willebrand disease type 3
Affected status: yes
Allele origin:
germline
|
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: SCV001572698.1 First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
Comment:
variant already reported in ClinVar
|
|
|
Pathogenic
(Apr 17, 2024)
|
no assertion criteria provided
Method: clinical testing
|
VWF-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005344938.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The VWF c.4975C>T variant is predicted to result in premature protein termination (p.Arg1659*). This variant has been well documented to be pathogenic for autosomal recessive … (more)
The VWF c.4975C>T variant is predicted to result in premature protein termination (p.Arg1659*). This variant has been well documented to be pathogenic for autosomal recessive Von Willebrand disease 3 (Ahmad et al. 2014. PubMed ID: 24712919; Borràs et al. 2017. PubMed ID: 28971901. Table S4; Gupta et al. 2008. PubMed ID: 18485763). This variant is reported in 0.040% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in VWF are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Academic Unit of Haematology, University of Sheffield
Accession: SCV000119026.1
First in ClinVar: Feb 21, 2014 Last updated: Feb 21, 2014 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
von Willebrand disorder
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV002507239.2
First in ClinVar: May 16, 2022 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
This nonsense variant causes the premature termination of VWF protein synthesis. In addition, it has been reported in individuals affected with VWD Type 3 in the published literature (PMID: 20147343 (2010), 24712919 (2014), 18485763 (2008), 23834637 (2013), 28971901 (2017), 24675615 (2014)). Therefore, the variant is classified as pathogenic.
Comment:
Variant summary: VWF c.4975C>T (p.Arg1659X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.6e-05 in 250392 control chromosomes. This frequency does not allow conclusions about variant significance. c.4975C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Von Willebrand Disease type 3 (example, Mohl_2011, Lapi_2022, Zhang_1992, Ahmad_2014). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
variant already reported in ClinVar
Comment:
The VWF c.4975C>T variant is predicted to result in premature protein termination (p.Arg1659*). This variant has been well documented to be pathogenic for autosomal recessive Von Willebrand disease 3 (Ahmad et al. 2014. PubMed ID: 24712919; Borràs et al. 2017. PubMed ID: 28971901. Table S4; Gupta et al. 2008. PubMed ID: 18485763). This variant is reported in 0.040% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in VWF are expected to be pathogenic. This variant is interpreted as pathogenic.
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. |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35505650, 31050121, 25525159, 1301136, 31589614, 29423401, 23834637, 9845532, 24712919, 18485763, 20147343)
Comment:
This nonsense variant causes the premature termination of VWF protein synthesis. In addition, it has been reported in individuals affected with VWD Type 3 in the published literature (PMID: 20147343 (2010), 24712919 (2014), 18485763 (2008), 23834637 (2013), 28971901 (2017), 24675615 (2014)). Therefore, the variant is classified as pathogenic.
Comment:
Variant summary: VWF c.4975C>T (p.Arg1659X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.6e-05 in 250392 control chromosomes. This frequency does not allow conclusions about variant significance. c.4975C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Von Willebrand Disease type 3 (example, Mohl_2011, Lapi_2022, Zhang_1992, Ahmad_2014). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
variant already reported in ClinVar
Comment:
The VWF c.4975C>T variant is predicted to result in premature protein termination (p.Arg1659*). This variant has been well documented to be pathogenic for autosomal recessive Von Willebrand disease 3 (Ahmad et al. 2014. PubMed ID: 24712919; Borràs et al. 2017. PubMed ID: 28971901. Table S4; Gupta et al. 2008. PubMed ID: 18485763). This variant is reported in 0.040% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in VWF are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Von Willebrand Disease. | Adam MP | - | 2024 | PMID: 20301765 |
| Next-generation sequencing of von Willebrand factor and coagulation factor VIII genes: a cross-sectional study in Croatian adult patients diagnosed with von Willebrand disease. | Lapić I | Croatian medical journal | 2022 | PMID: 35505650 |
| 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 |
| Association between Genetic Polymorphism and Risk of von Willebrand Disease in Pakistan. | Arshad N | BioMed research international | 2017 | PMID: 29423401 |
| Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients. | Borràs N | Haematologica | 2017 | PMID: 28971901 |
| 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 |
| Genetic heterogeneity in a large cohort of Indian type 3 von Willebrand disease patients. | Kasatkar P | PloS one | 2014 | PMID: 24675615 |
| 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 |
| Diagnosis and management of von Willebrand disease in Iran. | Cohan N | Seminars in thrombosis and hemostasis | 2011 | PMID: 22102206 |
| 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 |
| Coinheritance of severe von Willebrand disease with Glanzmann thrombasthenia. | Ahmad F | Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis | 2010 | PMID: 20147343 |
| Genetic defects in von Willebrand disease type 3 in Indian and Greek patients. | Gupta PK | Blood cells, molecules & diseases | 2008 | PMID: 18485763 |
| Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I. | Zhang ZP | American journal of human genetics | 1992 | PMID: 1415226 |
| 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 |
| click to load more click to collapse | ||||
Text-mined citations for rs61750595 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 19, 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.