AIPL1 p.Arg272Pro

NM_014336.5(AIPL1):c.815G>C (p.Arg272Pro) is a missense variant predicted to replace arginine with proline at amino acid p.272. This variant is absent from gnomAD v4.1.0 (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_014336.4:c.(?_-1)_(276+1_277-1)del variant suspected in trans (0.25 points, PMID: 30718709), which was previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP. The variant has also been reported in a second proband with early-onset severe retinal dystrophy who was heterozygous with no second AIPL1 variant identified in trans (PMID: 26626312). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with genotyping by next-generation sequencing panel targeting more than 150 inherited retinal disease-associated genes (2 pts), which together are not sufficiently specific for AIPL1-related retinopathy to meet PP4 (total 2.5 points, PMID: 30718709). The computational predictor REVEL gives a score of 0.692, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on AIPL1 protein function (PP3). The splicing impact predictor SpliceAI gives a score of 0.02 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3. (VCEP specifications version 1.0.0; date of approval 09/24/2025).