NM_000329.3(RPE65):c.143G>A (p.Gly48Glu) is a missense variant causing substitution of glycine with glutamic acid at position p.48. This variant is present in gnomAD v.4.1.1 at a total allele frequency of 6.19x10-7, with 1 allele / 1614088 total alleles in the total population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.859del variant confirmed in trans (PMID: 34492281), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset before age 1 year (1 pt), nystagmus (1 pt), night blindness with onset at age 1 year (0.5 pts), reduced visual fields (1 pt), reduced visual acuity (1 pt), diffuse retinal pigmentation, vascular thinning (0.5 pts), and optic disc pallor (0.5 pts), which together are specific for RPE65-related recessive retinopathy (6 total points, PMID: 34492281, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the compound heterozygous state (PP1_Moderate; PMID: 34492281). The computational predictor REVEL gives a score of 0.969, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_supporting, PM3, PP1_moderate, PP3_Moderate, and PP4. (LCA/eoRD VCEP specifications version 1.0.0)