ClinVar Genomic variation as it relates to human health

PS3

The VWF c.6859C>T; p.Arg2287Trp variant (rs61750625) is reported in the literature in individuals affected with von Willebrand disease (Goodeve 2007, Eikenboom 2009, Flood 2013), but has also been found in unaffected controls (Bellissimo 2012). Functional analyses of the variant protein show slightly impaired secretion (Flood 2013). This variant is reported in ClinVar (Variation ID: 100450) and is found in the African population with an allele frequency of 0.8% (199/24962 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.34). Due to limited information, the clinical significance of the p.Arg2287Trp variant is uncertain at this time. References: Bellissimo DB et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood. 2012 Mar 1;119(9):2135-40. PMID: 22197721. Eikenboom J et al. Expression of 14 von Willebrand factor mutations identified in patients with type 1 von Willebrand disease from the MCMDM-1VWD study. J Thromb Haemost. 2009 Aug;7(8):1304-12. PMID: 19566550. Flood VH et al. Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem. 2013 Apr;59(4):684-91. PMID: 23340442. Goodeve A et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood. 2007 Jan 1;109(1):112-21. PMID: 16985174.

Variant summary: VWF c.6859C>T (p.Arg2287Trp) results in a non-conservative amino acid change located in the VWFC domain (IPR001007) 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 0.00059 in 251052 control chromosomes in the gnomAD database, including 1 homozygotes. c.6859C>T has been reported in the literature in individuals affected with Von Willebrand Disease in settings of normal/inconsistent multimer results and normal/low VWF:CB, who also harbored other variants in the VWF gene (example, Kakela_2006, Goodeve_2007, Flood_2013, Sadler_2021, Dubois_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. At least one publication reports experimental evidence evaluating an impact on protein function (Eikenboom_2009). The most pronounced variant effect results in a mild-reduction in the levels of secreted VWF with no signs of intracellular retention leading to a categorization as "probably causative". The following publications have been ascertained in the context of this evaluation (PMID: 35734101, 19566550, 23340442, 16985174, 16321553, 33556167). ClinVar contains an entry for this variant (Variation ID: 100450). Based on the evidence outlined above, the variant was classified as uncertain significance.

Identified in multiple individuals with different subtypes of von Willebrand disease, including type 1, type 2M, and type 2A in the published literature, however, many individuals had other variants identified in VWF, and additional clinical or segregation information to support pathogenicity was not provided (PMID: 16321553, 16985174, 23340442); Published functional studies demonstrate a damaging effect with mild reduction in the amount of secreted VWF protein (PMID: 19566550); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19506359, 20981092, 24482836, 18344424, 16985174, 22197721, 22995991, 23216583, 23340442, 23690449, 19566550, 33556167, 35552711, 35734101, 16321553)

he frequency of this variant in the general population, 0.008 (199/24962 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with Type 1 or Type 2A von Willebrand disease (vWD) (PMID: 16985174 (2007), 23340442 (2013)), but it has also been reported in healthy individuals (PMID: 22197721 (2012), 23216583 (2013)). In in-vivo functional studies, this variant caused mild intracellular retention and impaired secretion of VWF protein (PMID: 16985174 (2007), 19566550 (2009), 23340442 (2013), 31035301 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.