ClinVar

Description

NM_000329.3(RPE65):c.1249G>C is a predicted missense variant substituting glutamic acid with glutamine at position 417. The computational predictor REVEL gives a score of 0.954, which is above the ClinGen LCA / eoRD VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In addition, the splicing impact predictor SpliceAI gives a score of 0.24 for acceptor gain, which is above the ClinGen LCA / eoRD VCEP recommended threshold of >=0.2 and predicts a damaging impact on splicing. This variant is present in gnomAD v.2.1.1 at a minor allele frequency of 0.000008825, with 1 allele / 113312 total alleles in the European non-Finnish 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 homozygous for the variant (0.5 points, PMID: 11462243, PMID: 20079931). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.11+5G>A variant confirmed in trans (1 point, VCEP member-provided data), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype that is highly specific for PE65-related recessive retinopathy (9 total points, VCEP member-provided data, PP4_Moderate). The variant exhibited 1-2% 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: 26427455, PMID: 16150724). 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: PS3_supporting, PM2_Supporting, PM3, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).