Variant: NM_000329.3(RPE65):c.235T>C (p.Tyr79His)

CA226528

98854 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 146ac98d-ec6a-4b8f-b4e0-94d7033dce69

Approved on: 2024-12-12

Published on: 2024-12-12

HGVS expressions

NM_000329.3:c.235T>C
NM_000329.3(RPE65):c.235T>C (p.Tyr79His)
NC_000001.11:g.68446720A>G
CM000663.2:g.68446720A>G
NC_000001.10:g.68912403A>G
CM000663.1:g.68912403A>G
NC_000001.9:g.68684991A>G
NG_008472.1:g.8240T>C
NG_008472.2:g.8240T>C
ENST00000262340.6:c.235T>C
ENST00000262340.5:c.235T>C
NM_000329.2:c.235T>C

Likely Pathogenic

• Met criteria codes: PP3_Moderate PS3_Supporting PP4 PM3_Supporting 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.235T>C (p.Tyr79His) variant is a missense variant in RPE65 causing a substitution of tyrosine with histidine at position 79. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 6.800e-7, with 3 alleles / 1180040 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). The computational predictor REVEL gives a score of 0.946, which is above the ClinGen LCA/ oRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 2.5% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 18599565). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.74C>T (p.Pro25Leu) variant suspected in trans, which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (0.5 total points, VCEP member-provided data, PM3_Supporting). The Pro25Leu and Tyr79His variants have also been reported in the compound heterozygous state in probands in multiple publications, but were not counted as additional cases as these may represent the same individual as above (PMIDs: 22807296, 30268864). The Pro25Leu variant has also been reported in the compound heterozygous state with the Glu95Gln and the Asp482Gly variants, but these cases were not counted due to insufficient phenotype and/or to avoid circularity in curation (PMID: 22807296, 11095629, 30268864, 17525851). At least one proband harboring this variant exhibits a phenotype including diagnosis of rod-cone dystrophy with congenital onset (1 pt), reduced central visual acuity (1 pt) multifocal ERG below threshold, no fundus autofluorescence (2 pts), nyctalopia, fine dots in the fundus, OCT preserved with respect to vision loss (1 pt), and paramacular photoreceptor thinning (5 total points, VCEP-member provided data, PP4). 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, PP3_Moderate, PP4, PM3_Supporting, PS3_Supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PP3_Moderate: The computational predictor REVEL gives a score of 0.946, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).
• PS3_Supporting: The variant exhibited 2.5% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 18599565).
• PP4: At least one proband harboring this variant exhibits a phenotype including diagnosis of rod-cone dystrophy with congenital onset (1 pt), reduced central visual acuity (1 pt) multifocal ERG below threshold, no fundus autofluorescence (2 pts), nyctalopia, fine dots in the fundus, OCT preserved with respect to vision loss (1 pt), and paramacular photoreceptor thinning (5 total points, VCEP-member provided data, PP4).
• PM3_Supporting: This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.74C>T (p.Pro25Leu) variant suspected in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, VCEP member-provided data, PM3_Supporting). The Pro25Leu and Tyr79His variants have also been reported in the compound heterozygous state in probands in multiple publications, but were not counted as additional cases as these may represent the same individual as above (PMIDs: 22807296, 30268864). The Pro25Leu variant has also been reported in the compound heterozygous state with the Glu95Gln and the Asp482Gly variants, but these cases were not counted due to insufficient phenotype and/or to avoid circularity in curation (PMID: 22807296, 11095629, 30268864, 17525851).
• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 6.800e-7, with 3 alleles / 1180040 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).