Clinical relevance of genetic variants in the von Willebrand factor according to in‐silico methods

Abstract

AbstractClinical interpretation of genetic variants in the context of the patient's phenotype is a time‐consuming and costly process. In‐silico analysis using in‐silico prediction tools, and molecular modeling have been developed to predict the influence of genetic variants on the quality and/or quantity of the resulting translated protein, and in this way, to alert clinicians of disease likelihood in the absence of previous evidence. Our objectives were to evaluate the success rate of the in‐silico analysis in predicting the disease‐causing variants as pathogenic and the single‐nucleotide variants as neutral, and to establish the reliability of in‐silico analysis for determining pathogenicity or neutrality of von Willebrand factor gene‐associated genetic variants. Using in‐silico analysis, we studied pathogenicity in 31 disease‐causing variants, and neutrality in 61 single‐nucleotide variants from patients previously diagnosed as type 2 von Willebrand disease. Disease‐causing variants and non‐synonymous single‐nucleotide variants were explored by in‐silico tools that analyze the amino acidic sequence. Intronic and synonymous single‐nucleotide variants were analyzed by in‐silico methods that evaluate the nucleotidic sequence. We found a consistent agreement between predictions achieved by in‐silico prediction tools and molecular modeling, both for defining the pathogenicity of disease‐causing variants and the neutrality of single‐nucleotide variants. Based on our results, the in‐silico analysis would help to define the pathogenicity or neutrality in novel genetic variants observed in patients with clinical and laboratory phenotypes suggestive of von Willebrand disease.