Endophenotype Effect Sizes Provide Evidence Supporting Variant Pathogenicity in Monogenic Disease Susceptibility Genes

ABSTRACT Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) are proxies for variant pathogenicity. Effect sizes were associated with pathogenic ClinVar assertions ( P <0.001 for each trait) and discriminated pathogenic from non-pathogenic variants (area under the curve 0.82-0.83 across endophenotypes). Large effect size thresholds provided evidence supporting pathogenicity for up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes, using an effect size threshold of ≥ 0.5 times the endophenotype standard deviation. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.