Variant: NM_000329.3:c.55G>A

CA340750220

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 7561359c-6530-4b00-a818-405ac597d9da

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.55G>A
NC_000001.11:g.68448663C>T
CM000663.2:g.68448663C>T
NC_000001.10:g.68914346C>T
CM000663.1:g.68914346C>T
NC_000001.9:g.68686934C>T
NG_008472.1:g.6297G>A
NG_008472.2:g.6297G>A
ENST00000262340.6:c.55G>A
ENST00000262340.5:c.55G>A
NM_000329.2:c.55G>A

Likely Pathogenic

• Met criteria codes: PP4_Moderate PM2_Supporting PM3 PP1

• Not Met criteria codes: PP3

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.55G>A (p.Val19Met) missense variant is predicted to replace the valine at position 19 with methionine. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pts) , decreased rod responses on ERG (0.5 pts), large gene panel testing without other significant findings (2 pts) , hypoautofluorescence (2 pts), optic nerve pallor (0.5 pts), pigmentary retinopathy (0.5 pts), posterior subcapsular cataract (0.5 pts), RPE mottling (0.5.pts), partial macular atrophy (0.5 pts), symptomatic onset before age 5 (1 pt), OCT preserved with respect to vision loss (1 pt), decreased peripheral vision (1 pt), ERG demonstrated cone involvement (1 pt), and decreased central visual acuity (1 pt) which together are highly specific for RPE65-related recessive retinopathy (total 12.5 points, PP4_Moderate).This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.65T>C (p.Leu22Pro) confirmed in trans (1 point) which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1.0 total points, PM3). 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).In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP4_Moderate, PM3, PP1. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PP4_Moderate: At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pts) , decreased rod responses on ERG (0.5 pts), large gene panel testing (2 pts) , hypoautofluorescence (2 pts), optic nerve pallor (0.5 pts), pigmentary retinopathy (0.5 pts), posterior subcapsular cataract (0.5 pts), RPE mottling (0.5.pts), partial macular atrophy (0.5 pts), symptomatic onset before age 5 (1 pt), OCT preserved with respect to vision loss (1 pt), decreased peripheral vision (1 pt), ERG demonstrated cone involvement (1 pt), and decreased central visual acuity (1 pt) which together are highly specific for RPE65-related recessive retinopathy (total 12.5 points, PP4_Moderate).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PM3: This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.65T>C (p.Leu22Pro) confirmed in trans (1 point) which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.0 total points, PM3).
• PP1: Patient has similarly affected sister who has been genotyped and is heterozygous for both the p.Val19Met and p.Leu22Pro variants.

Not Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.553, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.