ClinVar Miner

Submissions for variant NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys) (rs61749387)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000086703 SCV000889912 likely pathogenic not provided 2019-10-02 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851770 SCV000899705 pathogenic von Willebrand disorder 2019-02-01 criteria provided, single submitter research
Versiti Diagnostic Laboratories,Versiti, Inc RCV000000313 SCV001250574 pathogenic von Willebrand disease, type 2b 2019-07-09 criteria provided, single submitter clinical testing The missense variant VWF c.3922C>T, p.Arg1308Cys (p.R1308C; legacy p.R545C) in exon 28 changes amino acid arginine at codon 1308 to cysteine. The arginine at this residue is not well conserved among species. This amino acid change occurs in the A1 domain, a functional domain that binds GPIb (Springer, 2014). Pathogenic variants in VWF are associated with autosomal dominant or autosomal recessive von Willebrand disease (VWD), characterized by quantitative or qualitative deficiencies in von Willebrand factor and resulting in prolonged bleeding. This sequence variant has been previously reported in patients with type 2B von Willebrand disease (Randi, 1991; Ranger, 2012; Ahmad,2013; Frietas, 2019) and has been observed in multiple patients with type 2B von Willebrand disease in our laboratory cohort. Functional studies of the variant in mammalian cells show an increased affinity for GPIb or enhanced responsiveness with ristoceitin and preferential cleavage of high molecular weight multimers under fluid stress and natured conditions (Ahmad, 2013; Ma, 2015). To date, this variant has not been reported in the general population (gnomAD, Exome Variant Server). In summary, the collective evidence supports VWF c.3922C>T, p.Arg1308Cys as a dominant pathogenic variant for von Willebrand disease type 2B.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284955 SCV001471056 pathogenic none provided 2019-12-16 criteria provided, single submitter clinical testing The VWF c.3922C>T; p.Arg1308Cys variant (rs61749387), also known as R545C, is reported in the literature in multiple individuals affected with von Willebrand disease type 2B (Ahmad 2013, Baronciani 2005, Freitas 2019, Randi 1991, Ranger 2012). This variant is reported in ClinVar (Variation ID: 289), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 1308 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (Leu, Pro, Ser, His) have been reported in individuals with von Willebrand disease type 2B (Baronciani 2005, Hatta 2015, Meyer 1997, Nurden 2006). Based on available information, this variant is considered to be pathogenic. References: Ahmad F et al. Characterisation of mutations and molecular studies of type 2 von Willebrand disease. Thromb Haemost. 2013 Jan;109(1):39-46. Baronciani L et al. Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen binding. J Thromb Haemost. 2005 Dec;3(12):2689-94. Freitas SDS et al. Genetic variants of VWF gene in type 2 von Willebrand disease. Haemophilia. 2019 Mar;25(2):e78-e85. Hatta K et al. A family having type 2B von Willebrand disease with a novel VWF p.R1308S mutation: Detection of characteristic platelet aggregates on peripheral blood smears as the key aspect of diagnosis. Thromb Res. 2015 Oct;136(4):813-7. Meyer D et al. Gene defects in 150 unrelated French cases with type 2 von Willebrand disease: from the patient to the gene. INSERM Network on Molecular Abnormalities in von Willebrand Disease. Thromb Haemost. 1997 Jul;78(1):451-6. Nurden P et al. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia. Blood. 2006 Oct 15;108(8):2587-95. Randi AM 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 Apr;87(4):1220-6. Ranger A et al. Pregnancy in type 2B VWD: a case series. Haemophilia. 2012 May;18(3):406-12.
OMIM RCV000000313 SCV000020457 pathogenic von Willebrand disease, type 2b 2010-05-01 no assertion criteria provided literature only
Academic Unit of Haematology, University of Sheffield RCV000086703 SCV000118907 not provided not provided no assertion provided not provided

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