Reproducibility of the Evaluation of Genetic Variant Pathogenicity Based on the Animal Variant Classification Guidelines

ABSTRACT

Until recently, due to the absence of standardized guidelines tailored for veterinary use, the evaluation of genetic variant pathogenicity for single‐gene diseases was based on a personal interpretation of the presented evidence, which has led to inconsistencies. With the publication of the animal variant classification guidelines (AVCG), a more objective approach became available. Variants are evaluated by the International Society of Animal Genetics (ISAG)‐endorsed Variant Pathogenicity Working Group (VPWG) based on 23 criteria and are subsequently labeled as pathogenic, likely pathogenic, variant of uncertain significance, likely benign or benign. While the accuracy was thoroughly tested in the original publication, the reproducibility of the various steps involved was only briefly checked, which is why the current analysis was performed. Each variant from a set of 150 published likely causal variants for single‐gene diseases from three species (dog, cat, horse) was independently and blindly assessed by three different VPWG reviewers, each applying the same AVCG. An overall agreement of 93% for decisions on the scope, that is, whether they fit the inclusion criteria to allow evaluation with AVCG, was found. More importantly, the reproducibility of pathogenicity label assignment was 65% and the reproducibility of clinical relevance was 83%. The reproducibility of AVCG‐pathogenicity classification is in line with reports using the human American College for Medical Genetics and Genomics and Association for Molecular Pathology guidelines for human variants. Overall, the reproducibility of the AVCG classifications as used by the ISAG‐endorsed VPWG supports the utility of these classifications in veterinary species.