The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000329.3(RPE65):c.1451-1G>A

CA340741548

1321180 (ClinVar)

Gene: RPE65
Condition: RPE65-related recessive retinopathy
Inheritance Mode: Autosomal recessive inheritance
UUID: 8fd0d955-839f-471a-9a90-6773660c2412

HGVS expressions

NM_000329.3:c.1451-1G>A
NM_000329.3(RPE65):c.1451-1G>A
NC_000001.11:g.68429928C>T
CM000663.2:g.68429928C>T
NC_000001.10:g.68895611C>T
CM000663.1:g.68895611C>T
NC_000001.9:g.68668199C>T
NG_008472.1:g.25032G>A
NG_008472.2:g.25032G>A
ENST00000262340.6:c.1451-1G>A
ENST00000262340.5:c.1451-1G>A
NM_000329.2:c.1451-1G>A

Pathogenic

Met criteria codes 4
PP1_Moderate PP4 PM2_Supporting PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPE65 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_000329.3(RPE65):c.1451-1G>A is a canonical splice variant in intron 13 of RPE65 and is predicted to lead to the skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.000004024, with 1 allele / 6096 total alleles in the "Remaining Individuals" population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts), symptomatic onset between birth and age five years (1 pt), poor pupillary light response (0.5 pts), RPE mottling (0.5 pts), macular atrophy (0.5 pts), decreased central visual acuity (1 pt), pigmentary retinopathy with attenuated vessels (0.5 pts), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (total 5.5 points, PMID: 31957135, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through at least 2 affected meioses from 1 family, with the variant present in the homozygous state (PP1_Moderate; PMID: 31957135). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PP1_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Met criteria codes
PP1_Moderate
The variant has been reported to segregate with childhood-onset severe retinal dystrophy through at least 2 affected meioses from 1 family, with the variant present in the homozygous state (PP1_Moderate; PMID: 31957135).
PP4
At least one proband in harboring this variant exhibits a phenotype including, Clinical diagnosis of Leber congenital amaurosis (0.5) , Poor pupillary light response (0.5), RPE mottling (0.5), Macular atrophy (0.5), Decreased central visual acuity (1), Pigmentary retinopathy with attenuated vessels (0.5), Symptomatic onset between birth and age five years (1), Nystagmus (1) which together are highly specific for RPE65-related recessive retinopathy (total 5.5 points, PMID: 31957135, PP4).
PM2_Supporting
This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.000004024, with 1 allele / 6096 total alleles in the 'other' population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).
PVS1
This variant disrupts a canonical splice site in intron 13 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1).
Approved on: 2024-04-22
Published on: 2024-04-22
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