The NM_177438.2:c.4748T>G variant in DICER1 is a missense variant predicted to cause substitution of leucine by arginine at amino acid 1583 (p.Leu1583Arg). The variant has been reported to segregate with DICER1-related phenotypes in 3 affected family members from 1 family (PP1_moderate; PMID 19556464). This variant received a total of 1 phenotype point across 1 family meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID 19556464). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). In vitro cleavage assays in HEK293 cells showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (Wu 2018, McGill University) (PS3_Supporting). The computational predictor REVEL gives a score of 0.894, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP1_moderate, PS4_supporting, PM2_supporting, PS3_supporting, PP3. (Bayesian Points: 6; VCEP specifications version 1; 02/11/2022)