Variant: NM_000329.3(RPE65):c.1039C>T (p.Arg347Cys)

CA23569514

2149933 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 06a09501-373b-408b-b8e4-5abf194d015b

Approved on: 2024-12-12

Published on: 2024-12-12

HGVS expressions

NM_000329.3:c.1039C>T
NM_000329.3(RPE65):c.1039C>T (p.Arg347Cys)
NC_000001.11:g.68438276G>A
CM000663.2:g.68438276G>A
NC_000001.10:g.68903959G>A
CM000663.1:g.68903959G>A
NC_000001.9:g.68676547G>A
NG_008472.1:g.16684C>T
NG_008472.2:g.16684C>T
ENST00000262340.6:c.1039C>T
ENST00000262340.5:c.1039C>T
NM_000329.2:c.1039C>T

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP3_Moderate PP1_Moderate PM3_Supporting PP4

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.1039C>T (p.Arg347Cys) is a missense substitution, replacing arginine with cysteine at position 347. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.00000124, with 5 alleles / 1179740 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 0.789, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with onset of symptoms at age 4 months (1 pt), nystagmus (1 pt), pigmentary retinopathy with attenuated vessels (0.5 pts), decreased central visual acuity (1 pt), diminished rod (0.5 pts) and cone (1 pt) electroretinogram responses, poor pupillary light response (0.5 pts), and decreased peripheral vision (1 pt), which together are specific for RPE65-related recessive retinopathy (total 7 points, PMID: 36017377, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 36017377). This variant has been reported in 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points. PMID: 36017377, 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 variant p.Ala360Pro confirmed in trans (PMID: 33952291), which was not counted to avoid circularity. 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: PP1_moderate, PP3_moderate, PM2_supporting, PM3_supporting, 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 0.00000124, with 5 alleles / 1179740 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).
• PP3_Moderate: The computational predictor REVEL gives a score of 0.789, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).
• PP1_Moderate: The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 36017377).
• PM3_Supporting: This variant has been reported in 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points), PMID: 36017377). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the variant p.Ala360Pro confirmed in trans (PMID: 33952291), which has not been counted to avoid circularity (0.5 total points, PM3_Supporting).
• PP4: At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with onset of symptoms at 4 months of age (1 pt). Patient had nystagmus (1 pt), pigmentary retinopathy with attenuated vessels (0.5 pts), decreased central visual acuity (1 pt), diminished rod (0.5 pts ) and cone (1 pt) ERGs, poor pupillary light response (0.5 pts), and decreased peripheral vision (1 pt). Together these are specific for RPE65-related recessive retinopathy (total 7 points, PMID: 36017377, PP4)