ClinVar Genomic variation as it relates to human health

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.

PP5_very_strong, PS3

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 (PMID: 22507569); 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 (PMID: 25662333, 30565388); Identified in the heterozygous state in multiple unrelated individuals with features of von Willebrand disease but also observed in healthy control individuals (PMID: 22507569, 1672694, 31064749); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37872709, 1672694, 29924855, 34136746, 30565388, 31935285, 30690834, 28916584, 31064749, 28083987, 28971901, 23406206, 20409624, 34708896, 33556167, 24338593, 36754679, 22507569, 25662333)

VWF: PM5, BP4, BS1, BS2

ACMG Criteria: BS1, BS2, PS3, PM5, PP3, PP5; Variant found in a heterozygous state

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, Sadler_2021). 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, 33556167, 30565388). ClinVar contains an entry for this variant (Variation ID: 293). Based on the evidence outlined above, the variant was classified as uncertain significance.

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.