ClinVar Genomic variation as it relates to human health

PP1_Strong, PP3, PP5, PM2, PM6, PS3, PS4_Moderate

The VWF c.4789C>T; p.Arg1597Trp variant (also known as Arg834Trp in the mature protein, rs61750117) has been reported in patients with type 2A Von Willebrand disease (VWD) (Baronciani 2006, Ginsburg 1989, Starke 2013) and segregated with disease in a three-generation family (Shen 2016). In vitro studies have shown that this variant results in increased susceptibility to ADAMTS13 cleavage (Hassenpflug 2006, Pruss 2012, Pruss 2008). It has also been shown that plasma samples from patients carrying this variant lack high molecular weight multimers of Von Willebrand factor (VWF) (Hassenpflug 2006, Starke 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 285) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, several other variants at codon 1597 have been reported in patients with type 2A VWD (Donner 1993, Ginsburg 1993, Melo-Nava 2007, Veyradier 2016). The arginine at codon 1597 is highly conserved in the calcium-binding loop of VWF A2 domain (Xu 2013) and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Based on the above information, this variant is classified as pathogenic. References: Baronciani L et al. von Willebrand factor collagen binding assay in von Willebrand disease type 2A, 2B, and 2M. J Thromb Haemost. 2006 Sep; 4:2088-2090. Donner M et al. Two new candidate mutations in type IIA von Willebrand's disease (Arg834-->Gly, Gly846-->Arg) and one polymorphism (Tyr821-->Cys) in the A2 region of the von Willebrand factor. Eur J Haematol. 1993 Jul; 51:38-44. Ginsburg D et al. Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA. Proc Natl Acad Sci U S A. 1989 May; 86:3723-3727. Ginsburg D et al. von Willebrand disease: a database of point mutations, insertions, and deletions. For the Consortium on von Willebrand Factor Mutations and Polymorphisms, and the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1993 Feb 1; 69:177-184. Hassenpflug WA et al. Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. Blood. 2006 Mar 15; 107:2339-2345. Melo-Nava BM et al. Molecular study of VWF gene from Mexican Mestizo patients with von Willebrand disease, and the finding of three new mutations. Blood Cells Mol Dis. 2007 Nov-Dec; 39:361-365. Pruss CM et al. Use of a mouse model to elucidate the phenotypic effects of the von Willebrand factor cleavage mutants, Y1605A/M1606A and R1597W. J Thromb Haemost. 2012 May; 10:940-950. Pruss CM et al. ADAMTS13 cleavage efficiency is altered by mutagenic and, to a lesser extent, polymorphic sequence changes in the A1 and A2 domains of von Willebrand factor. Br J Haematol. 2008 Nov; 143:552-558. Shen MC et al. De novo mutation and somatic mosaicism of gene mutation in type 2A, 2B and 2M VWD. Thromb J. 2016 Oct 4; 14:36. Starke RD et al. Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells. Blood. 2013 Apr 4; 121:2773-2784. Veyradier A et al. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. Medicine (Baltimore). 2016 Mar; 95:e3038.

Variant summary: VWF c.4789C>T (p.Arg1597Trp) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251162 control chromosomes (gnomAD). c.4789C>T has been reported in the literature in multiple individuals affected with Von Willebrand Disease and the variant segregated with disease (examples: Ginsburg_1989, Inbal_1992, Starke_2013, and Shen_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence from in vitro and mouse model studies have demonstrated that this variant disrupts the normal activity of the protein (examples: Hassenpflug_2006, Xu_2013 and Pruss_2012). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=6) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

It has been reported in heterozygous individuals with von Willebrand disease (VWD) type 2A in the published literature (PMID: 19277422 (2009) and 16322474 (2006)) and has been reported to segregate with VWD type 2A in a large family (PMID: 27766062 (2016)). In addition, functional studies have demonstrated that this variant is damaging to VWF protein functions (PMID: 29186156 (2017), 22372972 (2012), 18986390 (2008), 16322474 (2006)). Therefore, this variant is classified as pathogenic.