Submissions for variant NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys)

gnomAD frequency: 0.00010  dbSNP: rs61750077

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852119	SCV000899726	likely pathogenic	Hereditary von Willebrand disease	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	Hereditary von Willebrand disease	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	RCV000086742	SCV001472382	likely pathogenic	not 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.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002222017	SCV002499570	likely pathogenic	von Willebrand disease type 2		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700405	SCV002572121	pathogenic	von Willebrand disorder	2024-07-09	criteria provided, single submitter	clinical testing	Variant summary: VWF c.4195C>T (p.Arg1399Cys) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250734 control chromosomes. c.4195C>T has been reported in the literature in individuals affected with Von Willebrand Disease (e.g: Gadisseur_2009, Fidalgo_2016, Downes_2019, Van Laer_2023, Maas_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31064749, 19506361, 34758185, 36696193, 26986123). ClinVar contains an entry for this variant (Variation ID: 100337). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV002222017	SCV004040782	likely pathogenic	von Willebrand disease type 2	2023-05-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000852119	SCV004848886	likely pathogenic	Hereditary von Willebrand disease	2023-02-02	criteria provided, single submitter	clinical testing	The p.Arg1399Cys (c.4195C>T) variant in VWF has been reported in at least 10 individuals with von Willebrand disease (Schneppenheim 2007, Maas 2022 PMID: 34758185, Fidalgo 2017 PMID: 28083987, Fidalgo 2016 PMID: 26988807, Downes 2019 PMID: 31064749, Baz 2021 PMID: 34272389). It has also been identified in 0.019%% (8/41414) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar (Variation ID 100337). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Laboratory data from patients in the studies cited above including platelet aggregation and VWF multimer analysis provides some evidence that this variant impacts protein function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant von Willebrand disease. ACMG/AMP Criteria applied: PS3, PS4_Moderate.
Mayo Clinic Laboratories, Mayo Clinic	RCV000086742	SCV005414040	likely pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	PP4, PP5, PM1_supporting, PS3, PS4_moderate
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002222017	SCV005418269	likely pathogenic	von Willebrand disease type 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PS4_Moderate+PP4_Moderate
Academic Unit of Haematology, University of Sheffield	RCV000086742	SCV000118948	not provided	not provided		no assertion provided	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV002222017	SCV002513410	likely pathogenic	von Willebrand disease type 2	2022-04-26	no assertion criteria provided	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000852119	SCV002515778	likely pathogenic	Hereditary von Willebrand disease		no assertion criteria provided	research