AIPL1 p.Val71Phe

NM_014336.5(AIPL1):c.211G>T (p.Val71Phe) is a missense variant resulting in replacement of valine by phenylalanine at amino acid p.71. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000001239, with 2 / 1,614,150 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 15024725, PMID: 20079931, PMID: 20702822, PMID: 26306921). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.216G>A (p.Trp72Ter) variant likely confirmed in trans due to their physical proximity (1 point, PMID: 20702822), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). The variant has been reported in an additional proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.730GAG[1] (p.Glu245del) variant suspected in trans, which has not yet been classified by the ClinGen LCA/eoRD VCEP. At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) received before age 5 years (1 pt), severely reduced central visual acuity (1 pt), kinetic visual field extent (V-4e) undetectable (1 pt), nystagmus (1 pt), and nondetectable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), which together are specific for AIPL1-related retinopathy (total 6 points, PMID: 20702822, PP4). The computational predictor REVEL gives a score of 0.780, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). 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. Co-expression of the variant with PDE6C and Pγ resulted in less than 10% of cGMP hydrolysis activity relative to the wild-type AIPL1 control (PMID: 27268253), while X-ray crystal structures of the wild-type and variant AIPL1 identified an inability of the variant to bind prenyl groups, which are relevant to AIPL1 interaction with the isoprenylated C-terminus of PDE6 (PMID: 28973376)(PS3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Strong, PP3_Moderate, PS3_supporting and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025).