Variant: NM_000329.3(RPE65):c.1292A>G (p.Tyr431Cys)

CA226500

29873 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 73c10d63-6456-4cf2-bf6b-506b7e13cfde

HGVS expressions

NM_000329.3:c.1292A>G
NM_000329.3(RPE65):c.1292A>G (p.Tyr431Cys)
NC_000001.11:g.68431328T>C
CM000663.2:g.68431328T>C
NC_000001.10:g.68897011T>C
CM000663.1:g.68897011T>C
NC_000001.9:g.68669599T>C
NG_008472.1:g.23632A>G
NG_008472.2:g.23632A>G
ENST00000262340.6:c.1292A>G
ENST00000262340.5:c.1292A>G
NM_000329.2:c.1292A>G

Likely Pathogenic

• Met criteria codes: PP4_Moderate PP3_Moderate PM3_Strong PM2_Supporting

• Not Met criteria codes: PM5

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.1292A>G is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 431. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002, with 1/113326 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 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.907A>T (p.Lys303Ter) or c.1102T>C (p.Tyr368His) variants confirmed in trans (2 point, PMIDs: 14962443, 30268864), which were 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 pts), absent or severely decreased rod electroretinogram responses (0.5 pts), congenital night blindness (0.5 pts), optic nerve pallor (0.5 pts), Pigmentary retinopathy with attenuated vessels (0.5 pts), macular atrophy (0.5 pts), symptomatic onset between birth and age five years (1 pt), decreased central visual acuity (1 pt), abnormal color vision or evidence of cone involvement on ERG (1 pt), nystagmus (1 pt), and significant improvement following gene therapy (8 pt) which together are highly specific for RPE65-related recessive retinopathy (PMIDs: 14962443, 19117922, 22323828, 15 points, PP4_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). 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/eoRP VCEP: PM3_Strong, PP4_Moderate, PM2_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PP4_Moderate: At least one proband harboring this variant exhibits a phenotype including Absent or severely decreased rod electroretinogram (ERG) responses (0.5 pt), Congenital night blindness/nyctalopia (0.5 pt), Clinical diagnosis of Leber congenital amaurosis (0.5 pt), Optic nerve pallor (0.5 pt), Pigmentary retinopathy with attenuated vessels (0.5 pt), Macular atrophy (0.5 pt), Symptomatic onset between birth and age five years (1 pt), Decreased central visual acuity (1 pt), Abnormal color vision or evidence of cone involvement on ERG (1 pt), Nystagmus (1 pt), and significant improvement following gene therapy (8 pt) which together are highly specific for RPE65-related recessive retinopathy (PMIDs: 14962443, 19117922, 22323828) (15 points, PP4_Moderate).
• PP3_Moderate: The computational predictor REVEL gives a score of 0.94, 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 gives a score of 0.02 for splice acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥ 0.2 and does not predict a damaging impact on splicing.
• PM3_Strong: This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.907A>T (p.Lys303Ter) or c.1102T>C (p.Tyr368His) variants confirmed in trans (2 point, PMIDs: 14962443, 30268864), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong).
• PM2_Supporting: This variant is present in gnomAD v.2.1.1 at a PopMax allele frequency of 0.00002, with 1/113326 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.002 (PM2_Supporting).

Not Met criteria codes

• PM5: c.1291T>C (p.Tyr431His) variant has been reported in ClinVar as VUS. Has not been evaluated by the LCA/eoRD VCEP

Approved on: 2024-01-31

Published on: 2024-01-31