Variant: NM_000329.3(RPE65):c.770T>G (p.Val257Gly)

Version: 1.0
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CA340745797

973967 (ClinVar)

Gene: RPE65 (HGNC:6121)

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 20d60fb3-a3a4-48fa-9715-c8c5955155b7

Approved on: 2025-06-30

Published on: 2025-06-30

HGVS expressions

NM_000329.3:c.770T>G
NM_000329.3(RPE65):c.770T>G (p.Val257Gly)
NC_000001.11:g.68439279A>C
CM000663.2:g.68439279A>C
NC_000001.10:g.68904962A>C
CM000663.1:g.68904962A>C
NC_000001.9:g.68677550A>C
NG_008472.1:g.15681T>G
NG_008472.2:g.15681T>G
ENST00000262340.6:c.770T>G
ENST00000262340.5:c.770T>G
NM_000329.2:c.770T>G

Likely Pathogenic

• Met criteria codes: PP4 PM2_Supporting PM3 PP3_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.770T>G (p.Val257Gly) is a missense variant predicted to replace valine with glycine at amino acid p.257. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has 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, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PMID: 40087508, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset between birth and age 5 years (1 pt), nystagmus (1 pt), flat electroretinogram responses from both rods (0.5 pts) and cones (1 pt), reduced best-corrected visual acuity (1 pt), and pigmentary retinopathy (0.5 pts), which together are specific for RPE65-related recessive retinopathy (total 5.5 points, PMID: 40087508, PP4). The computational predictor REVEL gives a score of 0.979, 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 0.01 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. 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, PM3, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PP4: At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset between birth and age 5 years (1 pt), nystagmus (1 pt), flat electroretinogram responses from both rods (0.5 pts) and cones (1 pt), reduced best-corrected visual acuity (1 pt), and pigmentary retinopathy (0.5 pts), which together are specific for RPE65-related recessive retinopathy (total 5.5 points, PMID: 40087508, PP4).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• PM3: This variant has 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, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PMID: 40087508, PM3).
• PP3_Moderate: The computational predictor REVEL gives a score of 0.979, 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 0.01 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.