ClinVar

Description

NM_000329.3(RPE65):c.394G>A is a missense variant that replaces alanine with threonine at codon 132. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01113, with 372 alleles / 30614 total alleles in the South Asian population (with 6 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The computational predictor REVEL gives a score of 0.548, which is above the ClinGen LCA / eoRD VCEP threshold of <0.3 and does not strongly predict a non-damaging effect on RPE65 function. The splicing impact predictor SpliceAI gives a score of 0.03 for splice acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of greater than or equal to 0.2 and does not strongly predict an impact on splicing. The variant exhibited 50% enzymatic activity in an isomerohydrolase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves] normal protein function (PMID: 16150724, BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).