ClinVar

Description

Variant summary: VWF c.3797C>A (p.Pro1266Gln) results in a non-conservative amino acid change located in the von Willebrand factor, VWA N-terminal domain (IPR032361) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 1612906 control chromosomes, predominantly at a frequency of 0.0039 within the South Asian subpopulation in the gnomAD database (v4.0.0), including 3 homozygotes. This frequency does not allow conclusions about variant significance.. c.3797C>A has been reported in the literature in individuals affected with Von Willebrand Disease as a component of gene conversion from the VWF pseudogene resulting in multiple alterations with normal levels of VWFGPIb-alpha/BC, normal platelet count before and after stress, normal platelet morphology, and a normal multimeric pattern (example, Federici_2009, Robertson_2011, Ahmad_2013, Casonato_2017, Alzahrani_2023). 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 in isolation (example Ahmad_2018). These results showed no damaging effect of this variant in isolation as all analysed qualitative and quantitative parameters of rVWF were comparable to WT. These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 30488424, 23179108, 37168293, 28640903, 18805962, 20371742, 21711445, 34807970). ClinVar contains an entry for this variant (Variation ID: 100279). Based on the evidence outlined above, the variant was classified as uncertain significance.