ClinVar Genomic variation as it relates to human health

The variant has been reported in multiple individuals with type 2B von Willebrand disease in the published literature (PMIDs: 31939074 (2020), 30817071 (2019), 1419803 (1992), and 2010538 (1991)). It has been shown to result in enhanced sensitivity to ADAMT13-mediated proteolysis (PMID: 26345337 (2015)), increased affinity for GpIbα, increased absence of high molecular weight multimers (PMIDs: 2010538 (1991), 16246252 (2005)), 23179108 (2013), 17155947 (2007)), and a reduced binding to collagen type I and III (PMID: 16246252 (2005)). Therefore, the variant is classified as pathogenic.

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 the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1308 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.673). 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. PMID: 23179108 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. PMID: 16246252 Freitas SDS et al. Genetic variants of VWF gene in type 2 von Willebrand disease. Haemophilia. 2019 Mar;25(2):e78-e85. PMID: 30817071 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. PMID: 26278967 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. PMID: 9198195 Nurden P et al. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia. Blood. 2006 Oct 15;108(8):2587-95. PMID: 16720832 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. PMID: 2010538 Ranger A et al. Pregnancy in type 2B VWD: a case series. Haemophilia. 2012 May;18(3):406-12. PMID: 22077376

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.

Variant summary: VWF c.3922C>T (p.Arg1308Cys) results in a non-conservative amino acid change located in the von Willebrand factor, type A (IPR002035) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251060 control chromosomes. c.3922C>T has been reported in the literature in multiple individuals affected with Von Willebrand Disease (Ahmad_2013, Casonato_2017, Ranger_2012). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function shows loss of high molecular weight multimers, increased affinity for GPIb and increased stability (Ahmad_2013, Ma_2015). The following publications have been ascertained in the context of this evaluation (PMID: 23179108, 28640903, 26345337, 22077376). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies demonstrate significantly increased GPIb binding in both homozygous and heterozygous states and moderately increased collagen binding (PMID: 23179108); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22077376, 1672694, 26345337, 31064749, 30924991, 30817071, 33556167, 35452508, 32573891, 31939074, 27766062, 23179108, 2010538, 36226571)

PP1, PP5, PM1, PM2_moderate, PS3, PS4_moderate