Submissions for variant NM_000552.5(VWF):c.4196G>A (p.Arg1399His)

gnomAD frequency: 0.00907  dbSNP: rs1800382

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756907	SCV000884884	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000756907	SCV000888698	uncertain significance	not provided	2023-02-03	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with hemophilia (PMID: 34708896 (2021)), Type 1 (PMID: 22507569 (2012)), and Type 2M Von Willebrand Disease (PMIDs: 33556167 (2021) and 29924855 (2018)). In addition, this variant has been reported in unaffected individuals (PMID: 33556167 (2021), 25662333 (2015), 1672694 (1991)). Functional studies for this variant found reduced static binding to collagen 4 and reduced platelet adhesion (PMID: 25662333 (2015)), as well as decreased binding to type VI collagen (PMID: 22507569 (2012), 30565388 (2019)). The frequency of this variant in the general population, 0.017 (173/10360 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV000756907	SCV001988044	uncertain significance	not provided	2021-10-12	criteria provided, single submitter	clinical testing	Published in vitro functional studies demonstrate a damaging effect with disrupted type VI collagen binding but no significant effect on type I or type III collagen binding (Flood et al., 2012); Published in vivo functional studies in mice demonstrate a damaging effect with reduced binding and adhesion of platelets to collagen IV leading to increased bleeding times (Flood et al., 2015; Slobodianuk et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23406206, 20409624, 28083987, 24338593, 1672694, 28971901, 29924855, 34136746, 30565388, 31935285, 30690834, 22507569, 25662333, 31064749, 28916584)
Mayo Clinic Laboratories, Mayo Clinic	RCV000756907	SCV002541191	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing	PP5_very_strong, PS3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234883	SCV003934653	uncertain significance	not specified	2024-01-18	criteria provided, single submitter	clinical testing	Variant summary: VWF c.4196G>A (p.Arg1399His) 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 allele was found at a frequency of 0.0086 in 250796 control chromosomes in the gnomAD database, including 21 homozygotes. c.4196G>A has been reported in the literature in both heterozygous and compound heterozygous individuals affected with Von Willebrand Disease (e.g., Flood_2012, Flood_2015, Nava_2019, Borras_2017). However, co-occurrences with other pathogenic variants have been reported, providing supporting evidence for either a benign role or a role in recessive disease (e.g., Flood_2012, Borras_2017). Several publications report experimental evidence evaluating an impact on protein function showing a complete disruption of binding to type VI collagen but no significant effect on type III collagen in vitro (Flood_2015, Flood_2012) as well as decreased collagen binding, decreased platelet adhesion, and increased bleeding times in a mouse model (e.g., Slobodianuk_2019). The following publications have been ascertained in the context of this evaluation (PMID: 28971901, 25662333, 22507569, 30690834, 30565388). ClinVar contains an entry for this variant (Variation ID: 293). Based on the conflicting evidence outlined above (high frequency and homozygotes in controls, reported patients with unclear inheritance, and damaging effect in functional studies), the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004547444	SCV004117563	uncertain significance	VWF-related disorder	2023-11-30	criteria provided, single submitter	clinical testing	The VWF c.4196G>A variant is predicted to result in the amino acid substitution p.Arg1399His. This variant was reported in healthy controls and in VWD type 1 and type 2 patients, some of whom had other likely pathogenic VWF gene variants (Borràs et al. 2017. PubMed ID: 28971901; Flood et al. 2015. PubMed ID: 25662333; Perez-Rodriquez et al. 2018. PubMed ID: 29924855). Amino acid residue p.Arg1399 resides in the VWF A1 collagen binding domain. Data in Flood et al. and in another report, Slobodianuk et al. 2018. PubMed ID: 30565388, indicate that the p.Arg1399His substitution decreases type IV and VI collagen binding. A similar variant, c.4195C>T (p.Arg1399Cys) was also reported in a patient with VWF 2m (Gadisseur et al. 2009. PubMed ID: 19506359). However, the p.Arg1399His substitution occurs frequently in several populations, including in the homozygous state, and is reported at frequencies ranging from ~ 0.2 -1.6%. Although we suspect that the c.4196G>A (p.Arg1399His) variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic information.
CeGaT Center for Human Genetics Tuebingen	RCV000756907	SCV004132416	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	VWF: PM5, BP4, BS1, BS2
Genetics and Molecular Pathology, SA Pathology	RCV003447466	SCV004175461	uncertain significance	von Willebrand disease type 2	2022-11-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000756907	SCV004237532	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing
OMIM	RCV000000317	SCV000020461	benign	VON WILLEBRAND FACTOR POLYMORPHISM	2010-05-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851940	SCV000899341	likely pathogenic	Abnormality of coagulation	2019-02-01	flagged submission	research
Laboratory of Genetic Engineering, National Medical Research Center for Hematology	RCV001270629	SCV001449495	likely benign	von Willebrand disease type 1	2020-01-01	no assertion criteria provided	research
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002243606	SCV002515777	pathogenic	Hereditary von Willebrand disease		flagged submission	research