FIGURE 1.

Model and methods for weighting phenotype evidence for variant interpretation. (a) In our model, phenotype evidence was categorized and weighted based on the likelihood that the cause of a condition had a known genetic etiology. When a high percentage of individuals with the same collection of clinical features were shown to have pathogenic variants indicating a molecular diagnosis, the phenotype was considered highly predictive. As shown in the lower left quadrant, the phenotype of an individual alone was less predictive of a known genetic basis, so classification could only rely on observation of the variant segregating in a family of individuals with similar clinical features, a separate type of evidence in the ACMG/AMP guidelines and Sherloc (Richards et al., 2015; Nykamp et al., 2017) (b) To determine the appropriate category of phenotype evidence for gene(s) associated with a condition, we followed a systematic curation workflow. Phenotype includes clinical signs and symptoms, either individually or in combination