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_014336.5(AIPL1):c.34dup (p.Val12fs)

CA8328680

813151 (ClinVar)

Gene: AIPL1 (HGNC:23746)

Condition: AIPL1-related retinopathy (MONDO:0100438)

Inheritance Mode: Autosomal recessive inheritance

UUID: d883da51-7056-4ff2-b2fa-7e196697c22c

Approved on: 2025-09-29

Published on: 2025-09-29

HGVS expressions

NM_014336.5(AIPL1):c.34dup (p.Val12fs)

NM_014336.5:c.34dup

NC_000017.11:g.6435074dup

CM000679.2:g.6435074dup

NC_000017.10:g.6338394dup

CM000679.1:g.6338394dup

NC_000017.9:g.6279118dup

NG_008474.1:g.5129dup

ENST00000381129.8:c.34dup

ENST00000250087.9:c.34dup

ENST00000381128.2:c.34dup

ENST00000381129.7:c.34dup

ENST00000570466.5:c.34dup

ENST00000570584.5:c.9dup

ENST00000571740.5:c.34dup

ENST00000574506.5:c.34dup

ENST00000574913.1:c.34dup

ENST00000575265.5:c.34dup

ENST00000576307.5:c.34dup

ENST00000576776.5:c.34dup

ENST00000621374.4:c.34dup

NM_001033054.2:c.34dup

NM_001033055.2:c.34dup

NM_001285399.2:c.34dup

NM_001285400.2:c.34dup

NM_001285401.2:c.34dup

NM_001285402.1:c.-142dup

NM_001285403.2:c.34dup

NM_014336.4:c.34dup

NM_001033054.3:c.34dup

NM_001033055.3:c.34dup

NM_001285399.3:c.34dup

NM_001285400.3:c.34dup

NM_001285401.3:c.34dup

NM_001285402.2:c.-142dup

NM_001285403.3:c.34dup

NM_001285403.4:c.34dup

Likely Pathogenic

PVS1 PM2_Supporting

PP4 PM3

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.34dup (p.Val12GlyfsTer?) is a 1 bp duplication that changes amino acid p.12 from valine to glycine and alters the reading frame, with a new stop codon encountered after 32 amino acids. This premature stop codon in exon 1 of 6 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 present in gnomAD v.4.1.0 at a total allele frequency of 0.000001859, with 3 /1614036 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 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 32531858). However, the proband was not counted for PM3_Supporting because the other variant p.Arg80Trp is currently classified as a VUS and was not confirmed to be in trans. 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: PVS1 and PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025).

PVS1

This is a frameshift variant that introduces a premature stop codon into exon 1 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).

PM2_Supporting

This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000001859, with 3 /1614036 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting).

PP4

Patient diagnosed with LCA (0.5 pts), no additional phenotype description.

PM3

This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 32531858). However, the proband was not counted for this criterion because the other variant p.Arg80Trp is currently classified as a VUS and was not confirmed to be in trans. PM3_Supporting requires at least 0.5 total points, so this criterion was not met.

Curation History

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