Variant: NM_000329.3(RPE65):c.74C>T (p.Pro25Leu)

CA902628

437985 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 9ffc6fee-a8f4-44ab-b142-5c93b283144f

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.74C>T
NM_000329.3(RPE65):c.74C>T (p.Pro25Leu)
NC_000001.11:g.68448644G>A
CM000663.2:g.68448644G>A
NC_000001.10:g.68914327G>A
CM000663.1:g.68914327G>A
NC_000001.9:g.68686915G>A
NG_008472.1:g.6316C>T
NG_008472.2:g.6316C>T
ENST00000262340.6:c.74C>T
ENST00000262340.5:c.74C>T
NM_000329.2:c.74C>T

Pathogenic

• Met criteria codes: PM3_Strong PP3_Moderate PS3_Supporting PM2_Supporting PP4_Moderate

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.74C>T is a missense variant predicted to replace proline with leucine at position 25 in exon 2 of RPE65. 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, PMIDs: 18599565). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were either compound heterozygous with the c.893del p.Lys298fs variant confirmed in trans (1 pt), with the Arg515Trp variant suspected in trans (0.5 pts), or with the c.11+5G>A variant suspected in trans (0.5 pts), PMIDs: 35001204, 36672611, 30025081), which were all previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). This variant has also been reported in additional probands in the compound heterozygous state with the Ala434Glu or Tyr79His variants, but these cases were not considered to avoid circularity in the application of the PM3 code or due to insufficient phenotype data (PMIDs 29033008, 32581362, 22807296). At least one proband harboring this variant exhibits a phenotype including significant, documented improvement of dark-adapted vision after treatment with RPE65 gene therapy (8 pt), congenital night blindness (0.5 pt), nystagmus (1 pt), decreased central visual acuity (1 pt), and onset between birth and age five years (1 pt), which together are highly specific for RPE65-related recessive retinopathy (11.5 points, PMID: 36672611, PP4_Moderate). The variant exhibited 7.75% 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). The computational predictor REVEL gives a score of 0.898, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.0001, with 1/30582 total alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_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: PM3_Strong, PP3_Moderate, PP4_Moderate, PS3_Supporting, PM3_Supporting (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 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID 18599565). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were either compound heterozygous with the c.893del p.Lys298fs variant confirmed in trans (1 pt), with the Arg515Trp variant suspected in trans (0.5 pts), or with the c.11+5G>A variant suspected in trans (0.5 pts), PMIDs: 35001204, 36672611, 30025081), which were all previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). This variant has also been reported in additional probands in the compound heterozygous state with the Ala434Glu or Tyr79His variants, but these cases were not considered to avoid circularity in the application of the PM3 code or due to insufficient phenotype data (PMIDs 29033008, 32581362, 22807296).
• PP3_Moderate: The computational predictor REVEL gives a score of 0.898, 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 7.75% 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).
• PM2_Supporting: This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.0001, with 1/30582 total alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).
• PP4_Moderate: At least one proband harboring this variant exhibits a phenotype including Significant, documented improvement of dark-adapted vision after treatment with RPE65 gene therapy (8 pt), congenital night blindness (0.5 pt), nystagmus (1 pt), decreased central visual acuity (1 pt), and onset between birth and age five years (1 pt), which together are highly specific for RPE65-related recessive retinopathy (11.5 points, PMID: 36672611, PP4_Moderate).