ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.4135C>T (p.Arg1379Cys)
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.4135C>T (p.Arg1379Cys)
Variation ID: 100333 Accession: VCV000100333.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6019283 (GRCh38) [ NCBI UCSC ] 12: 6128449 (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 Aug 4, 2024 Jan 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.4135C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Arg1379Cys missense NM_000552.4:c.4135C>T NC_000012.12:g.6019283G>A NC_000012.11:g.6128449G>A NG_009072.2:g.110388C>T LRG_587:g.110388C>T LRG_587t1:c.4135C>T LRG_587p1:p.Arg1379Cys - Protein change
- R1379C
- Other names
- p.R1379C
- Canonical SPDI
- NC_000012.12:6019282: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00004
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
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 |
1518 | 1572 |
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
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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, multiple submitters, no conflicts
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Jan 11, 2023 | RCV000086738.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2022 | RCV000778378.8 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jul 14, 2021 | RCV002243738.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 10, 2020 | RCV002264660.4 | |
VWF-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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- | RCV003335097.1 |
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. |
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Pathogenic
(Oct 23, 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: SCV000914597.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The VWD c.4135C>T (p.Arg1379Cys) missense variant has been reported in at least five studies in which is found in at least 19 individuals with von … (more)
The VWD c.4135C>T (p.Arg1379Cys) missense variant has been reported in at least five studies in which is found in at least 19 individuals with von Willebrand disease (VWD) including in four in a compound heterozygous state, and in 15 in a heterozygous state (six of which are related) (Casana et al. 2001; Goodeve et al. 2007; Casonato et al. 2010; Johansson et al. 2011; Casonato et al. 2015). The p.Arg1379Cys variant was shown to segregate with disease in a clear autosomal dominant pattern in one family with unclassified VWD and a phenotype of mild bleeding by its presence in six affected individuals and absence from three unaffected individuals (Casana et al. 2001). At least seven of the unrelated heterozygotes had an atypical form of VWD type 2B (Casonato et al. 2010; Casonato et al. 2015). Three of the compound heterozygotes presented with VWD type 1 and all carried a different missense variant on the second allele (Johansson et al. 2011). The p.Arg1379Cys variant was absent from 187 controls (Johansson et al. 2011) and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Arg1379 residue is conserved. Based on the evidence, the p.Arg1379Cys variant is classified as pathogenic 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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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: SCV002546312.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Number of individuals with the variant: 1
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Pathogenic
(Aug 04, 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: SCV002571747.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: VWF c.4135C>T (p.Arg1379Cys) results in a non-conservative amino acid change located in the first type A domain (IPR002035) of the encoded protein sequence. … (more)
Variant summary: VWF c.4135C>T (p.Arg1379Cys) results in a non-conservative amino acid change located in the first type A domain (IPR002035) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250330 control chromosomes (gnomAD). c.4135C>T has been reported in the literature in heterozygous state in multiple individuals affected with Von Willebrand Disease (VWD) type 1 and type 2B (e.g. Pagliari_2016, Casana_2001, Veyradier_2016, Casonato_2017), and in one of these reports the variant showed segregation with the phenotype in a large family (Casana_2001). The variant was also reported in cis (i.e. as a complex allele) with the variant c.4130C>T (p.Ala1377Val) in 4 unrelated patients with type 2M VWD (Pagliari_2016). This publication also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant Arg1379Cys resulted in an increased glycoprotein Ib-alpha (GP1BA) binding, however, when it was expressed in cis (as a complex allele) with Ala1377Val, it abolished GP1BA binding, resulting in type 2M VWD phenotype (Pagliari_2016). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, partly without evidence for independent evaluation, and all laboratories classified the variant as pathogenic (n=4) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 11, 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: SCV000521093.5
First in ClinVar: Mar 08, 2017 Last updated: Jan 21, 2023 |
Comment:
Functional studies show R1379C enhances binding capacity to the glycoprotein Ib-alpha (Pagliari et al., 2016); In silico analysis supports that this missense variant has a … (more)
Functional studies show R1379C enhances binding capacity to the glycoprotein Ib-alpha (Pagliari et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20305138, 19630772, 16783784, 26986123, 23775583, 19453940, 26456374, 27532107, 18230755, 16985174, 19277422, 27353798, 21534937, 19506353, 31589614, 31939074, 11325649, 27785872) (less)
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Pathogenic
(-)
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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: SCV004013122.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023
Comment:
Submitted to the GoldVariant database by Kathleen Freson, Center for Molecular and Vascular Biology
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Clinical Features:
bleeding (present)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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VWF-related disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046395.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a heterozygous and compound heterozygous change in patients with VWF-related disorders (PMID: 11325649, 27785872, 16985174, 19277422, 26986123, 31939074). … (more)
This variant has been previously reported as a heterozygous and compound heterozygous change in patients with VWF-related disorders (PMID: 11325649, 27785872, 16985174, 19277422, 26986123, 31939074). Functional studies show the p.Arg1379Cys variant enhances binding capacity to the glycoprotein Ib-alpha (PMID: 27785872). This variant was shown to segregate with disease in an autosomal dominant manner in at least one family with VWF-related disorder and a phenotype of mild bleeding (PMID: 20305138). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/281706) and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.4135C>T (p.Arg1379Cys) variant is classified as Pathogenic. (less)
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Likely pathogenic
(Jul 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 2
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175520.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
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Pathogenic
(Jun 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: SCV002563096.14
First in ClinVar: Aug 23, 2022 Last updated: Aug 04, 2024 |
Comment:
VWF: PS3, PS4, PM2, PP1
Number of individuals with the variant: 1
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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: SCV002513393.1
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: SCV000118944.1
First in ClinVar: Feb 25, 2014 Last updated: Feb 25, 2014 |
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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: SCV002507232.2
First in ClinVar: May 11, 2022 Last updated: Oct 01, 2022 |
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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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Type 2B von Willebrand disease with or without large multimers: A distinction of the two sides of the disorder is long overdue. | Casonato A | PloS one | 2017 | PMID: 28640903 |
von Willebrand Disease. | Adam MP | - | 2017 | PMID: 20301765 |
von Willebrand disease type 1 mutation p.Arg1379Cys and the variant p.Ala1377Val synergistically determine a 2M phenotype in four Italian patients. | Pagliari MT | Haemophilia : the official journal of the World Federation of Hemophilia | 2016 | PMID: 27785872 |
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 |
Higher and lower active circulating VWF levels: different facets of von Willebrand disease. | Casonato A | British journal of haematology | 2015 | PMID: 26456374 |
Variation in the VWF gene in Swedish patients with type 1 von Willebrand Disease. | Johansson AM | Annals of human genetics | 2011 | PMID: 21534937 |
Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia. | Casonato A | Haematologica | 2010 | PMID: 20305138 |
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 |
New mutations in exon 28 of the von Willebrand factor gene detected in patients with different types of von Willebrand's disease. | Casaña P | Haematologica | 2001 | PMID: 11325649 |
Text-mined citations for rs61750074 ...
HelpRecord last updated Aug 04, 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.