The NM_000329.3(RPE65):c.361dup (p.Ser121fs) frameshift variant introduces a premature stop codon in exon 5 of 14 and is predicted to trigger nonsense-mediated decay (PVS1). It is reported in the literature in a compound heterozygous state in at least one proband (by whole exome sequencing) who was diagnosed with Leber congenital amaurosis and exhibits infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), flat rod ERG (required, 1 pt), and flat cone ERG (1 pt), which together is highly specific for RPE65-related recessive retinopathy (PMID: 30870047, PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP4_Moderate, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023)