Variant: NM_000329.3(RPE65):c.726-2A>T

CA340745897

952461 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: b03d1b9c-6057-4a0a-b153-99da49246a87

Approved on: 2025-03-27

Published on: 2025-03-27

HGVS expressions

NM_000329.3:c.726-2A>T
NM_000329.3(RPE65):c.726-2A>T
NC_000001.11:g.68439325T>A
CM000663.2:g.68439325T>A
NC_000001.10:g.68905008T>A
CM000663.1:g.68905008T>A
NC_000001.9:g.68677596T>A
NG_008472.1:g.15635A>T
NG_008472.2:g.15635A>T
ENST00000262340.6:c.726-2A>T
ENST00000262340.5:c.726-2A>T
NM_000329.2:c.726-2A>T

Pathogenic

• Met criteria codes: PVS1 PP1 PP4_Moderate PS1_Supporting PM2_Supporting

• Not Met criteria codes: PM3

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 RPE65 Version 1.0.0

Evidence submitted by expert panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

The NM_000329.3(RPE65):c.726-2A>T variant occurs at a canonical splice site in intron 7. It is predicted to lead to skipping of a critical exon, resulting in a frameshift, and likely 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 Grpmax allele frequency of 6.800e-7 , with 3 alleles / 1179940 total alleles in the European (non-Finnish) 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 a diagnosis of LCA (0.5 pts) with nystagmus (1 pt), myopia, retinal degeneration at 2-years-old (1 pt), sluggish pupillary responses (0.5 pts), extensive atrophic retinal changes, salt and pepper fundus appearance (2 pts), optic disc pallor, and extinguished rod and cone ERG (1.5 pts). Screening by NGS did not reveal any additional variants of interest (2 pts). Together these phenotypes are highly specific for RPE65-related recessive retinopathy (total 8.5 points, PMID: 33308271, PP4_moderate).The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 33308271).This variant is located at the splice acceptor +/-1,2 dinucleotide position and has a comparable Pathogenic variant at the +/-1,2 dinucleotide (NM_000329.3(RPE65):c.726-2A>C).(PS1_supporting). 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, PP4_moderate, PP1, PS1_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PVS1: This variant disrupts a canonical splice site in intron 7. It is predicted to lead to skipping of a critical exon, resulting in a frameshift, and likely nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1).
• PP1: The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 33308271).
• PP4_Moderate: At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with nystagmus (1 pt), myopia, retinal degeneration at 2-years-old (1 pt), sluggish pupillary responses (0.5 pts), extensive atrophic retinal changes, salt and pepper fundus appearance (2 pts), optic disc pallor, and extinguished rod and cone ERG (1.5 pts). Screening by NGS did not reveal any additional variants of interest (2 pts). Together these phenotypes are highly specific for RPE65-related recessive retinopathy (total 8.5 points, PMID: 33308271, PP4_Moderate).
• PS1_Supporting: This variant is located at the splice acceptor +/-1,2 dinucleotide position and has a comparable Pathogenic variant at the +/-1,2 dinucleotide (NM_000329.3(RPE65):c.726-2A>C).(PS1_supporting)
• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 6.800e-7 , with 3 alleles / 1179940 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).

Not Met criteria codes

• 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: 33308271). However, the proband was not counted for this criterion because the other variant in trans has not yet been classified and counts for only 0.25 pts towards PM3. PM3_Supporting requires at least 0.5 total points, so this criterion was not met.