Variant: NM_000329.3(RPE65):c.715T>G (p.Tyr239Asp)

CA226579

98889 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 862029ef-cc5c-4b10-b102-f9a252e48910

HGVS expressions

NM_000329.3:c.715T>G
NM_000329.3(RPE65):c.715T>G (p.Tyr239Asp)
NC_000001.11:g.68439571A>C
CM000663.2:g.68439571A>C
NC_000001.10:g.68905254A>C
CM000663.1:g.68905254A>C
NC_000001.9:g.68677842A>C
NG_008472.1:g.15389T>G
NG_008472.2:g.15389T>G
ENST00000262340.6:c.715T>G
ENST00000262340.5:c.715T>G
NM_000329.2:c.715T>G

Pathogenic

• Met criteria codes: PM3_Strong PP4_Moderate PP3_Moderate PM2_Supporting PS3_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

NM_000329.3(RPE65):c.715T>G is a predicted missense variant substituting tyrosine by aspartic acid at position 239. The computational predictor REVEL gives a score of 0.987, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI also gives a score of 0.34 for splice acceptor gain, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002, with 3/129118 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 3 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 32032261). 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.1102T>C (p.Tyr368His) variant confirmed in trans (1 point, PMID: 26626312), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt) and significant, documented improvement of blue full-field stimulus testing after treatment with RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (8.5 points, PMID: 21911650, PP4_Moderate). The variant exhibited between 1% (PMID: 24849605) and 5% (PMID: 19431183) enzymatic activity in retinoid isomerase assays 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). 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: PS3_Supporting, PM2_Supporting, PM3_Strong, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PM3_Strong: This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 32032261). 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.1102T>C (p.Tyr368His) variant confirmed in trans (1 point, PMID: 26626312), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong).
• PP4_Moderate: At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber Congenital Amaurosis (0.5 pt) and significant, documented improvement of Blue FST after treatment with RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (8.5 points, PMID: 21911650, PP4_Moderate).
• PP3_Moderate: The computational predictor REVEL gives a score of 0.987, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). SpliceAI also gives a score of 0.34 for splice acceptor gain, consistent with a deleterious effect on splicing.
• PM2_Supporting: This variant is present in gnomAD v.2.1.1 at a PopMax allele frequency of 0.00002323, with 3/129118 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).
• PS3_Supporting: The variant exhibited a severe defect in enzymatic activity in a retinoid isomerase assay (PS3_Supporting, PMID: 19431183).

Approved on: 2024-02-18

Published on: 2024-02-18