ClinVar Miner

Submissions for variant NM_000552.4(VWF):c.3916C>T (p.Arg1306Trp) (rs61749384)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000086699 SCV000602302 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000086699 SCV000884886 pathogenic not provided 2017-09-20 criteria provided, single submitter clinical testing The VWF c.3916C>T, p.Arg1306Trp variant (also known as Arg534Trp) is reported in the medical literature in multiple families affected by von Willebrand disease type IIB (Cooney 1991, Lillicrap 1991, Pietu 1991, Randi 1991, Donner 1992, Casana 1998, Ozeki 2010) and co-segregates with affected family members (Lillicrap 1991, Donner 1992, Casana 1998). Functional characterization of the p.Arg1306Trp protein indicates a greater sensitivity to shear stress, leading to a reduction of high molecular weight multimers in plasma (Scaglione 2013). The variant is listed in the ClinVar database (Variation ID:288) and the dbSNP variant database (rs61749384), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The arginine at residue 1306 is moderately conserved, and computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on protein structure or function. Based on the above information, the variant is classified as pathogenic. References: Casana P et al. Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants. Am J Hematol. 1998 59(1):57-63. Cooney K et al. The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain. J Clin Invest. 1991 87(4):1227-33. Donner M et al. Type IIB von Willebrand's disease: gene mutations and clinical presentation in nine families from Denmark, Germany and Sweden. Br J Haematol. 1992 82(1):58-65. Lillicrap D et al. Recurring mutations at CpG dinucleotides in the region of the von Willebrand factor gene encoding the glycoprotein Ib binding domain, in patients with type IIB von Willebrand's disease. Br J Haematol. 1991 79(4):612-7. Ozeki M et al. A family having type 2B von Willebrand disease with an R1306W mutation: Severe thrombocytopenia leads to the normalization of high molecular weight multimers. Thromb Res. 2010 125(2):e17-22. Pietu G et al. Molecular study of von Willebrand disease: identification of potential mutations in patients with type IIA and type IIB. Blood Coagul Fibrinolysis. 1992 3(4):415-21. Randi A et al. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. J Clin Invest. 1991 87(4):1220-6. Scaglione G et al. The type 2B p.R1306W natural mutation of von Willebrand factor dramatically enhances the multimer sensitivity to shear stress. J Thromb Haemost. 2013 11(9):1688-98.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851599 SCV000899333 pathogenic von Willebrand disorder 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851989 SCV000899702 pathogenic von Willebrand disease type 2 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851990 SCV000899703 likely pathogenic Abnormality of coagulation 2019-02-01 criteria provided, single submitter research
Versiti Diagnostic Laboratories,Versiti, Inc RCV000000312 SCV001250575 pathogenic von Willebrand disease, type 2b 2018-05-14 criteria provided, single submitter clinical testing The missense variant VWF c.3916C>T, p.Arg1306Trp (p.R1306W) in exon 28 changes amino acid arginine at codon 1306 to tryptophan. The arginine at this residue is somewhat conserved among species. This amino acid change occurs in the A1 domain, a functional domain that binds GP1ba and collagen (Springer, 2014). This sequence variant has been previously reported in patients with type 2B von Willebrand disease (Cooney, 1991; Randi, 1991; Ozeki, 2010) and has been observed in multiple patients with type 2B VWD in our laboratory cohort. Functional studies of the variant in mammalian cells demonstrated significantly increased platelet binding in the presence and absence of ristocetin (Cooney, 1996) and dramatic enhancement of multimer sensitivity to shear stress. (Scaglione, 2013). To date, this variant has not been reported in the general population (GnomAD, Exome Variant Server). In summary, the collective evidence supports VWF c.3916C>T, p.Arg1306Trp as a pathogenic variant for type 2B von Willebrand disease.
OMIM RCV000000312 SCV000020456 pathogenic von Willebrand disease, type 2b 2010-05-01 no assertion criteria provided literature only
Academic Unit of Haematology, University of Sheffield RCV000086699 SCV000118903 not provided not provided no assertion provided not provided

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