The feline variant classification guideline (FVCG): an objective tool to evaluate the genetic variant pathogenicity

Background: the correct classification of a variant as pathogenic is important as breeding decisions based on invalid DNA tests can lead to the incorrect exclusion of animals and potentially compromise the long-term health of a population. In human medicine, the American College of Medical Genetics and Genomics guideline (ACMGG) provides a framework for variant classification. However, questions on the transferability to veterinary medicine have been raised. Aim: to develop a cohesive variant classification guideline that can be used by the community for feline Mendelian disorders to classify variants in categories based on scientific evidence. Methods: a stepwise approach was adopted in which experts were individually asked to evaluate the ACMGG and propose new criteria. Next, these evaluations were jointly discussed and led to the “feline variant classification guideline” (FVCG). The FVCG and ACMGG are benchmarked for a set of variants that were unanimously considered pathogenic by at least three independent experts. Results: from the original 28 criteria in the ACMGG, seven were removed, seven adapted and 14 retained. One criterion was added. Together, this led to 22 criteria in the FVCG. Sixty pathogenic variants are used for benchmarking. Conclusions: half of the ACMGG criteria were deemed unsuitable in its current form. New criteria have been developed and their performance is assessed. This collaborative approach led to a tool that can provide guidance to researchers, clinical geneticists, and laboratories to objectively determine when sufficient evidence is present to consider a feline Mendelian variant pathogenic.