ClinVar

Description

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.