ClinVar

Description

NM_000329.3(RPE65):c.907A>T (p.Lys303Ter) is a nonsense variant that introduces a premature stop codon into exon 9 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with infantile onset (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), absence of electroretinogram responses from rods (0.5 pts) and cones, nystagmus (1 pt), loss of color vision (1 pt), severely constricted visual fields (1 pt), optic nerve head pallor (0.5 pts), attenuation of retinal arterioles (0.5 pts) with pigmentary changes, macular atrophy (0.5 pts), and significant improvement of dark-adapted vision following RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (15.5 total pts, PMID: 14962443, PMID: 22323828, PP4_Moderate). 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, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).