Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001285403.4:c.126T>A

CA397397658

Gene: AIPL1 (HGNC:23746)

Condition: AIPL1-related retinopathy (MONDO:0100438)

Inheritance Mode: Autosomal recessive inheritance

UUID: df7ed658-ed3d-4088-99d8-99fb3f290094

Approved on: 2025-09-29

Published on: 2025-09-29

HGVS expressions

NM_001285403.4:c.126T>A

NC_000017.11:g.6434069A>T

CM000679.2:g.6434069A>T

NC_000017.10:g.6337389A>T

CM000679.1:g.6337389A>T

NC_000017.9:g.6278113A>T

NG_008474.1:g.6131T>A

ENST00000381129.8:c.126T>A

ENST00000250087.9:c.126T>A

ENST00000381128.2:c.184T>A

ENST00000381129.7:c.126T>A

ENST00000570466.5:c.97-37T>A

ENST00000570584.5:c.101T>A

ENST00000571740.5:c.126T>A

ENST00000574506.5:c.97-7T>A

ENST00000574913.1:c.126T>A

ENST00000575265.5:c.126T>A

ENST00000576307.5:c.96+940T>A

ENST00000576776.5:c.126T>A

ENST00000621374.4:c.126T>A

NM_001033054.2:c.126T>A

NM_001033055.2:c.96+940T>A

NM_001285399.2:c.97-7T>A

NM_001285400.2:c.97-37T>A

NM_001285401.2:c.126T>A

NM_001285402.1:c.9T>A

NM_001285403.2:c.126T>A

NM_014336.4:c.126T>A

NM_001033054.3:c.126T>A

NM_001033055.3:c.96+940T>A

NM_001285399.3:c.97-7T>A

NM_001285400.3:c.97-37T>A

NM_001285401.3:c.126T>A

NM_001285402.2:c.9T>A

NM_001285403.3:c.126T>A

NM_014336.5:c.126T>A

Pathogenic

PM2_Supporting PVS1 PM3_Supporting PP4

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

NM_014336.5(AIPL1):c.126T>A (p.Cys42Ter) is a nonsense variant that introduces a premature stop codon into exon 2 of 6 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). 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_014336.5(AIPL1):c.784G>A (p.Gly262Ser) variant suspected but not confirmed in trans (0.5 points, PMID: 15249368), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (PM3_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with visual acuity limited to hand movements (1 pt), mild maculopathy (0.5 pts), mild optic nerve pallor (0.5 pts), severe pigmentary retinopathy (1 pt), and photoattraction (1 pt), which together are specific for AIPL1-related retinopathy (total 4.5 points, PMID: 15249368, PP4). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PM3_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PVS1

This is a nonsense variant that introduces a premature stop codon into exon 2 of 6 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1).

PM3_Supporting

This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.784G>A (p.Gly262Ser) variant suspected but not confirmed in trans (0.5 points, PMID: 15249368), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (PM3_Supporting).

PP4

At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with visual acuity limited to hand movements (1 pt), mild maculopathy (0.5 pts), mild optic nerve pallor (0.5 pts), severe pigmentary retinopathy (0.5 pts), and photoattraction (1 pt), which together are specific for AIPL1-related recessive retinopathy (total 4 points, PMID: 15249368, PP4).

Curation History

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