ClinVar Miner

Submissions for variant NM_000552.4(VWF):c.4195C>T (p.Arg1399Cys) (rs61750077)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852119 SCV000899726 likely pathogenic von Willebrand disorder 2019-02-01 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000086742 SCV001134902 uncertain significance not provided 2020-04-22 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000852119 SCV001437518 likely pathogenic von Willebrand disorder 2020-04-27 criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in patients with Type 2M Von Willebrand disease (VWD2M, PMID: 170008851, 26988807, 31064749). It has also been seen together with other variants in the same gene in patients with Type 2U Von Willebrand disease (PMID: 19506359, 28083987). Functional characterization of the p.Arg1399Cys variant indicated normal VWF antigen level (VWF:Ag), mildy reduced ristocetin cofactor activity (VWF:RCo) resulting in a smeared appearance of the multimer (no clear separation between individual oligomer triplets), and significantly reduced VWF collagen type VI binding (VWF:CVIB) (PMID: 28083987). ClinVar contains an entry for this variant (Variation ID: 100337). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (8/282104) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.4195C>T (p.Arg1399Cys) variant on protein function. Based on the available evidence, the c.4195C>T (p.Arg1399Cys) variant is classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285880 SCV001472382 likely pathogenic none provided 2019-10-27 criteria provided, single submitter clinical testing The VWF c.4195C>T; p.Arg1399Cys variant (rs61750077) is reported in the literature in multiple individuals affected with an unclassifiable type of von Willebrand disease (Fidalgo 2016, Michiels 2006, Schneppenheim 2007, Wang 2012). This variant is reported in ClinVar (Variation ID: 100337), and is only observed on eight alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1399 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate a smeary multimer pattern that suggests the introduced cysteine residue may interfere with disulfide bonds (Fidalgo 2016, Schneppenheim 2007), and at least one patient had vWF activity below the level of detection (Michiels 2006). Based on available information, this variant is considered to be likely pathogenic. References: Fidalgo T et al. Genotype-phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS. Thromb Haemost. 2016 Jul 4;116(1):17-31. Michiels JJ et al. Classification and characterization of hereditary types 2A, 2B, 2C, 2D, 2E, 2M, 2N, and 2U (unclassifiable) von Willebrand disease. Clin Appl Thromb Hemost. 2006 Oct;12(4):397-420. Schneppenheim R et al. Molecular Background of “Smeary” von Willebrand Factor Multimers. Blood. 2007 110(11):2711. Wang JW et al. Biogenesis of Weibel-Palade bodies in von Willebrand's disease variants with impaired von Willebrand factor intrachain or interchain disulfide bond formation. Haematologica. 2012 Jun;97(6):859-66.
Academic Unit of Haematology, University of Sheffield RCV000086742 SCV000118948 not provided not provided no assertion provided not provided

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