Variant: NM_014336.5(AIPL1):c.401A>T (p.Tyr134Phe)

Version: 1.0
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CA202389

196465 (ClinVar)

Gene: AIPL1 (HGNC:23746)

Condition: AIPL1-related retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: adf46226-3417-4578-ad21-3a2053d9c0df

Approved on: 2025-09-29

Published on: 2025-09-29

HGVS expressions

NM_014336.5:c.401A>T
NM_014336.5(AIPL1):c.401A>T (p.Tyr134Phe)
NC_000017.11:g.6428382T>A
CM000679.2:g.6428382T>A
NC_000017.10:g.6331702T>A
CM000679.1:g.6331702T>A
NC_000017.9:g.6272426T>A
NG_008474.1:g.11818A>T
ENST00000381129.8:c.401A>T
ENST00000250087.9:c.277-1325A>T
ENST00000381128.2:c.*273A>T
ENST00000381129.7:c.401A>T
ENST00000570466.5:c.335A>T
ENST00000570584.5:c.251+5537A>T
ENST00000571740.5:c.401A>T
ENST00000574506.5:c.365A>T
ENST00000574913.1:c.401A>T
ENST00000575265.5:c.401A>T
ENST00000576307.5:c.221A>T
ENST00000576776.5:c.401A>T
ENST00000621374.4:c.401A>T
NM_001033054.2:c.277-1325A>T
NM_001033055.2:c.221A>T
NM_001285399.2:c.365A>T
NM_001285400.2:c.335A>T
NM_001285401.2:c.401A>T
NM_001285402.1:c.284A>T
NM_001285403.2:c.401A>T
NM_014336.4:c.401A>T
NM_001033054.3:c.277-1325A>T
NM_001033055.3:c.221A>T
NM_001285399.3:c.365A>T
NM_001285400.3:c.335A>T
NM_001285401.3:c.401A>T
NM_001285402.2:c.284A>T
NM_001285403.3:c.401A>T
NM_001285403.4:c.401A>T

Benign

• Met criteria codes: BA1 BS2 PP3_Moderate

• Not Met criteria codes: BS3

Expert Panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for AIPL1 Version 1.0.0

Evidence submitted by expert panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

NM_014336.5(AIPL1):c.401A>T (p.Tyr134Phe) is a missense variant in exon 3 of 6 that is predicted to replace tyrosine with phenylalanine at amino acid p.134. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.006905, with 8,298 alleles / 1,180,030 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1). It has also been found in the homozygous state in 49 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.845, 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 delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing. The variant exhibited >90% enzymatic activity in a cGMP hydrolysis assay relative to the wild-type control, as well as cytoplasmic and nuclear localization similar to the wild-type (PMID: 27268253), however, these assays are not approved to meet BS3_Supporting. In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025).

Met criteria codes

• BA1: This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.006905, with 8298 alleles /1180030 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1).
• BS2: This variant has been found in the homozygous state in 49 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2).
• PP3_Moderate: The computational predictor REVEL gives a score of 0.845, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function. However, the in silico data is conflicting with an AlphaMissense score of 0.1054 supporting a benign variant, while other models are indeterminate. In addition, the splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing. Because the variant meets the BA1 code and the BS2 code with 49 homozygotes, the PP3 code is not used.

Not Met criteria codes

• BS3: The variant exhibited >90% enzymatic activity in a cGMP hydrolysis assay relative to the wild-type control, as well as cytoplasmic and nuclear localization similar to the wild-type (PMID: 27268253), however, these assays are not approved to meet BS3_Supporting.