As a researcher working on variant interpretation pipelines, I’m curious about the scoring matrix used to prioritize pathogenic variants. Specifically, how were the relative weights for gene-disease association, population frequency, and phenotype match determined? Were these weights empirically calibrated using a training set or validated against known clinical cases? Without a documented benchmarking or sensitivity analysis, how can we be confident that the scoring system reliably reflects clinical relevance, especially in cases involving variable expressivity or novel gene associations?
