Variant: NM_000329.3(RPE65):c.859del

CA2497030002

1213917 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 2513f264-dcac-4500-a13c-32e471b9028d

HGVS expressions

NM_000329.3:c.859del
NM_000329.3(RPE65):c.859del
NC_000001.11:g.68439082del
CM000663.2:g.68439082del
NC_000001.10:g.68904765del
CM000663.1:g.68904765del
NC_000001.9:g.68677353del
NG_008472.1:g.15879del
NG_008472.2:g.15879del
ENST00000262340.6:c.859del
ENST00000262340.5:c.859del
NM_000329.2:c.859del

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PP4 PP1_Moderate

• 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

NM_000329.3(RPE65):c.859delG (p.Val287PhefsTer38) is a frameshift variant that introduces a premature stop codon into exon 9 of 14, 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 v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a clinical diagnosis of Leber congenital amaurosis (0.5 pts), loss of visual acuity (1 pt) since age 1 year (1 pt), nystagmus (1 pt), night blindness (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), and pale optic disc (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5 points, PMID: 34492281, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the compound heterozygous state (PMID: 34492281, PP1_moderate). 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, and PP1_moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PVS1: c.859delG (p.Val287PhefsTer38) in exon 9 of RPE65 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9/14 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP4: At least one patient harboring this variant exhibits a clinical diagnosis of Leber congenital amaurosis and a phenotype including visual loss since age 1 year (1pt), nystagmus (1 pt), night blindness (0.5 pts), loss of visual acuity (1pt), pigmentary retinopathy with attenuated vessels (0.5 pts) and pale optic disc (0.5 pts), which together are specific for RPE65-related recessive retinopathy (4.5 points, PMID: 34492281, PP4).
• PP1_Moderate: The variant has been reported to segregate with RPE65 retinopathy in the proband plus two affected siblings, all with a compound heterozygous genotype with Gly48Glu and c.859delG variants (PMID: 34492281).

Not Met criteria codes

• PM3: LCA-0068 II:1 is compound heterozygous for Gly48Glu and c.859delG (not considered here to avoid circularity).

Approved on: 2024-02-20

Published on: 2024-02-20