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

CA10581648

236480 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 6a052841-acea-4876-a5fd-bbac04ac3f2b

Approved on: 2025-03-27

Published on: 2025-03-27

HGVS expressions

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

Pathogenic

• Met criteria codes: PM3_Supporting PVS1 PM2_Supporting

• Not Met criteria codes: PP4

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>C 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 total allele frequency of 0.0000006199, with 1 allele / 91072 alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points), PMID: 27208204). (0.5 total points, PM3_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, PM3_supporting.(VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PM3_Supporting: This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points), PMIDs: 27208204). (0.5 total points, PM3_Supporting).
• 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).
• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0000006199, with 1 allele / 91072 alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).

Not Met criteria codes

• PP4: At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA/eoRD (0.5 pts), and was tested by NGS using a large retinal gene panel with no other likely pathogenic variants identified (2 pts), which is not sufficiently specific for RPE65-related recessive retinopathy to meet the PP4 code (total 2.6 points, PMID: 27208204).