EP354: A systematic approach for applying disease-specific phenotype in clinical variant interpretation

Abstract

The 2015 ACMG/AMP clinical variant interpretation guidelines incorporate an individual’s phenotype, including presenting features and family history consistent with a particular genetic cause of disease, across multiple pathogenicity criteria. However, they do not give detailed guidance on how to define or weight such disease-specific features, leading to uncertainty and discordant use in clinical variant interpretation. Here, we assessed the recommendations of existing ClinGen Variant Curation Expert Panels (VCEPs) for applying phenotypic data for their associated gene-disease pairs, and used this to create a broader framework to support more systematic use of phenotypic features in clinical variant interpretation.