ClinVar

Description

NM_000329.3(RPE65):c.1451-1G>A is a canonical splice variant in intron 13 of RPE65 and is predicted to lead to the skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.000004024, with 1 allele / 6096 total alleles in the "Remaining Individuals" population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts), symptomatic onset between birth and age five years (1 pt), poor pupillary light response (0.5 pts), RPE mottling (0.5 pts), macular atrophy (0.5 pts), decreased central visual acuity (1 pt), pigmentary retinopathy with attenuated vessels (0.5 pts), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (total 5.5 points, PMID: 31957135, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through at least 2 affected meioses from 1 family, with the variant present in the homozygous state (PP1_Moderate; PMID: 31957135). 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, PM2_Supporting, PP1_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).