As an additional aid, the DVD integrates predictions from six algorithms—two assessing conservation (PhyloP and GERP++) and four evaluating deleteriousness (SIFT, PolyPhen-2, MutationTaster, and LRT)—from which to calculate a composite PS. As more than 95% of known P variants have a pathogenicity score > 40%, the PPV of this approach reaches 0.995 (Figure S1). Using this threshold, we classify variants as either VUS (PS ≥ 60%) or LB (PS ≤ 40%). ACMG guidelines also endorse predictions from in silico algorithms as one of the eight evidence criteria recommended for variant clinical interpretation, and although outcomes and results from several studies vary depending on the algorithms used, these studies all agree on the utility of such tools for improving accuracy and reducing VUS burden in clinical diagnosis.3, 26