Variant: NM_000329.3(RPE65):c.1078G>C (p.Ala360Pro)

CA226480

98823 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 9ee1484f-82bf-4018-ae20-2f7ca818ed01

Approved on: 2024-12-12

Published on: 2024-12-12

HGVS expressions

NM_000329.3:c.1078G>C
NM_000329.3(RPE65):c.1078G>C (p.Ala360Pro)
NC_000001.11:g.68438237C>G
CM000663.2:g.68438237C>G
NC_000001.10:g.68903920C>G
CM000663.1:g.68903920C>G
NC_000001.9:g.68676508C>G
NG_008472.1:g.16723G>C
NG_008472.2:g.16723G>C
ENST00000262340.6:c.1078G>C
ENST00000262340.5:c.1078G>C
NM_000329.2:c.1078G>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM3_Strong PP4 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

NM_000329.3(RPE65):c.1078G>C is a missense variant predicted to replace alanine with proline at position 360. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000001240, with 5 alleles / 1179942 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). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.1282_1303del (p.Gly428MetfsTer5) or NM_000329.3(RPE65):c.1039C>T (p.Arg347Cys) variants confirmed in trans (PMID: 19431183, PMID: 33952291), both were previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP (2 points total, PM3_strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) by next-generation sequencing-based genotyping of a panel of 586 eye disease-associated genes (2 pts), congenital onset (1 pt), reduced central visual acuity (1 pt), extinct ERG responses from rods (0.5 pts) and cones (1 pt), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (7 pts total, PMID: 33952291, PP4). The computational predictor REVEL gives a score of 0.677, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3). 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, PM3_Strong, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000001240, with 5 alleles / 1179942 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).
• PM3_Strong: This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.1282_1303del (p.Gly428MetfsTer5) or NM_000329.3(RPE65):c.1039C>T (p.Arg347Cys) variants confirmed in trans (PMID: 19431183, PMID: 33952291), both were previously classified likely pathogenic by the ClinGen LCA / eoRD VCEP (2 points total, PM3_strong). This variant has been reported in at least 1 proband with a diagnosis of retinitis pigmentosa who harbored the variant in the homozygous state (PMID: 25097241). However, the proband was not counted for PM3 because sufficient phenotype details to establish severity were unavailable.
• PP4: At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) by next-generation sequencing-based genotyping of a panel of 586 eye disease-associated genes (2 pts), congenital onset (1 pt), reduced central visual acuity (1 pt), extinct ERG responses from rods (0.5 pts) and cones (1 pt), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (7 pts total, PMID: 33952291, PP4).
• PP3: The computational predictor REVEL gives a score of 0.677, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3).