NM_000329.3:c.997G>C

CA340744560

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 83319959-d7b1-4a3d-8e55-fae18ead6d56

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.997G>C
NC_000001.11:g.68438943C>G
CM000663.2:g.68438943C>G
NC_000001.10:g.68904626C>G
CM000663.1:g.68904626C>G
NC_000001.9:g.68677214C>G
NG_008472.1:g.16017G>C
NG_008472.2:g.16017G>C
ENST00000262340.6:c.997G>C
ENST00000262340.5:c.997G>C
NM_000329.2:c.997G>C

Likely Pathogenic

• Met criteria codes: PP4 PM3 PP3_Moderate PM2_Supporting

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.997G>C (p.Gly333Arg) 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: 33952291). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.1059dupG p.Lys354fs variant confirmed in trans (1 point, PMIDs: 31273949, 21602930), which was previously classified pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt), congenital night blindness (0.5 pt), absent decreased rod ERG responses (0.5 pt), evidence of cone involvement on ERG (1 pt), symptomatic onset between birth and age five years (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt), which together are specific for RPE65-related recessive retinopathy (4 points, PMID: 31273949 & 21602930, PP4). This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.0001925, with 1 / 5194 total allele in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.867, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_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: PM3, PP3_Moderate, PM2_Supporting, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PP4: At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt), congenital night blindness (0.5 pt), absent decreased rod ERG responses (0.5 pt), evidence of cone involvement on ERG (1 pt), symptomatic onset between birth and age five years (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt), which together are specific for RPE65-related recessive retinopathy (4 points, PMID: 31273949 & 21602930, PP4).
• PM3: 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: 33952291). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.1059dupG p.Lys354fs variant confirmed in trans (1 point, PMIDs: 31273949, 21602930), which was previously classified pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3).
• PP3_Moderate: The computational predictor REVEL gives a score of 0.867, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).
• PM2_Supporting: This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.0001925, with 1 / 5194 total allele in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).