ClinVar Genomic variation as it relates to human health

NM_000329.3(RPE65):c.1253T>A is a missense variant predicted to replace phenylalanine with tyrosine at position 418. This variant is absent from gnomAD v2.1.1 (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.997G>C (p.Gly333Arg) variant confirmed in trans, which was previously classified as likely pathogenic by the ClinGen LCA / eoRD VCEP (1 point, PMID: 34830511, PM3). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pt), symptomatic onset between birth and age five years (1 pt), decreased central visual acuity (1 pt), nystagmus (1 pt), macular dystrophy (0.5 pt), and absent ERG responses from rods (0.5 pt) and cones (1 pt), which together are specific for RPE65-related recessive retinopathy (5.5 points, PMID: 34830511, PP4). The computational predictor REVEL gives a score of 0.895, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 22745121). 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: PS3_Supporting, PM2_Supporting, PM3, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).