Question special
Lead Moderator

I'd like to leverage off of Julie's question yesterday and ask about classifying variant pathogenicity. As all of us in human genetics are well aware, determining whether a variant is pathogenic is an incredibly challenging task. What criteria are used for determining whether a variant is pathogenic? Given that many "Mendelian" variants are now known to be quite incompletely penetrant, how is the reduced penetrance taken into account? Also, variants often have markedly different effects depending on family history (e.g. Factor V Leiden), ethnic background, and other factors. How are these additional factors taken into account? Is ClinGen working to develop new tools to facilitate this process?