AIPL1 p.Cys239Arg

NM_014336.5(AIPL1):c.715T>C (p.Cys239Arg) is predicted to replace the cysteine at position p.239 with arginine. 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 homozygous for the variant (PMID: 15249368) (0.5 total points, PM3_Supporting). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 15249368 and personal communication). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with poor central vision (1 pt) from birth (1 pt), along with severe night blindness (0.5 pts) and pendular nystagmus (1 pt). Full-field electroretinogram responses were non-detectable from both rods (0.5 pts) and cones (1 pt). Visual acuity 20/800 in both eyes at age 17. Fundus examination revealed widespread RPE changes with pigment clumping (0.5 pt), attenuated retinal vessels (1 pt), macular atrophy (0.5 pts) and a pale optic disk (0.5 pts) which together are specific for AIPL1-related retinopathy (total 8 points, PMID: 10873396, PP4_Moderate). The variant protein exhibits less than 10% of wild-type AIPL1 activity in a cGMP hydrolysis assay based on exogenous expression in HEK293T cells (PMID: 27268253, PS3_Supporting). the computational predictor REVEL gives a score of 0.789, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). 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, PP3_Moderate, PS3_Supporting, PM3_Supporting, PP1_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025).