AIPL1

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0100438

Submitter: ClinGen

*AIPL1* was first reported in relation to autosomal recessive Leber congenital amaurosis in 2000 (Sohochi et al., PMID: 10615133). *AIPL1* has been associated with autosomal recessive cone-rod dystrophy, juvenile retinitis pigmentosa, and Leber congenital amaurosis [OMIM#604393]. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, the aforementioned disease entities have been lumped into one disease entity, AIPL1-related retinopathy. 11 variants (of variant types including missense, deletion, nonsense, and frameshift) that have been reported in nine probands in four publications (PMIDs: 10615133, 25596619) are included in this curation. Notably, the c.834G>A (p.Trp278Ter) nonsense variant (ClinVar variation ID: 5565) has been reported to be a common variant in this gene (Aboshiha et al., PMID: 25596619). Functional studies have demonstrated that this p.Trp278Ter nonsense variant alters cellular function, affecting the modulation of NUB1, a downstream target of AIPL1 (van der Spuy et al., PMID: 15347646). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Additional functional studies have demonstrated that missense variants (such as c.784G>A (p.Gly262Ser)) can lead to abnormal splicing of transcript (Bellingham et al., PMID: 26650897). This gene-disease association is also supported by mouse models, in which AIPL1-deficient mice have displayed retinal degeneration (Dyer et al., PMIDs: 15582159). In summary, *AIPL1* is definitively associated with AIPL1-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on February 2nd, 2023 (SOP Version 9).

Inheritance Pattern: SD

Disease ID:MONDO:0100438

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0019118

Submitter: ClinGen

*AIPL1* variants were first reported in relation to retinal disease in 2000 (Sohocki et al., PMID: 10873396). While *AIPL1* has been definitively associated with autosomal recessive retinopathy by the ClinGen Retinal Gene Curation Expert Panel, the single variant asserted to be associated with autosomal dominant inheritance was excluded from that curation. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the reported autosomal dominant cases were found to differ from the more established autosomal recessive cases in their mode of inheritance but to overlap in phenotype. The decision was made to split and curate them separately, with the recessive cases curated under AIPL1-related autosomal recessive retinopathy, and the asserted dominant cases evaluated in the present curation for inherited retinal dystrophy with autosomal dominant inheritance. The single variant that has been asserted to show autosomal dominant inheritance is an in-frame deletion, AIPL1:c.1053_1064del (p.Ala352_Pro355del). This variant is present at a frequency in gnomAD v4.1.0 that is inconsistent with a role as a primary cause of dominant disease, with over 1000 heterozygotes and 3 homozygotes. To date, *in vitro* functional studies have not supported a role for the in-frame deletion in subcellular localization or protein binding (PMID: 33067476). A transgenic mouse model expressing primate AIPL1 c.1053_1064del has been generated and the mice demonstrate retinal degeneration (PMID: 25274777). However, no additional evidence has been presented to support pathogenicity of heterozygous variants in AIPL1. While a number of other *AIPL1* variants have been identified in the heterozygous state in individuals with retinal disease, evidence for pathogenicity of these variants was not supportive of their role in disease (PMID: 3067476). In In summary, preliminary evidence is sufficient to classify the association between *AIPL1* and autosomal dominant inherited retinal dystrophy as Disputed. Additional studies are needed either to support the association of heterozygous AIPL1 variants with retinal disease, or to refute the causality of these variants in the reported cases. This classification has been approved by the ClinGen Retina GCEP on April 3rd, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0011458

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0011458

Submitter: G2P