Variant: NM_000329.3(RPE65):c.1418T>A (p.Val473Asp)

CA226515

98846 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: d1b42d5c-6dd4-4376-b088-49da0241c349

HGVS expressions

NM_000329.3:c.1418T>A
NM_000329.3(RPE65):c.1418T>A (p.Val473Asp)
NC_000001.11:g.68431097A>T
CM000663.2:g.68431097A>T
NC_000001.10:g.68896780A>T
CM000663.1:g.68896780A>T
NC_000001.9:g.68669368A>T
NG_008472.1:g.23863T>A
NG_008472.2:g.23863T>A
ENST00000262340.6:c.1418T>A
ENST00000262340.5:c.1418T>A
NM_000329.2:c.1418T>A

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PM3_Strong PP3_Moderate

• Not Met criteria codes: BS1 BA1

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.1418T>A is a missense variant that substitutes valine with arginine at position 473. This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 9501220, SCV001430890.1). This variant has also been reported in at least 1 probands with early-onset severe retinal dystrophy who was compound heterozygous with the p.Pro363Thr variant confirmed in trans (1 point, VCEP member-provided data), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one patient harboring the variant exhibits a phenotype including nondetectable ERG responses from rods (0.5 pts) and cones ( 1 pt), nyctalopia (0.5 pts), decreased central visual acuity (1 pt), symptomatic onset between birth and age 5 years (1 pt), light staring (1 pt), and positive response to RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (13 total points, VCEP member-provided data, PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.992, which is above the ClinGen LCA/eoRD VCEP PP3_Mod 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 a Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD 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

• PM2_Supporting: This variant is absent from gnomAD v2.1.1. (PM2_Supporting).
• PP4_Moderate: At least one patient harboring the variant exhibited reduced or nondetectable rod ERG (required, 2 pts), decreased central visual acuity (1 pt), symptomatic onset between birth and age 5 years (1 pt), evidence of cone involvement on ERG (1 pt), light staring (1 pt), nyctalopia (1 pt), and positive response to RPE65 gene therapy (8 pts), exceeding the 8 phenotype points required for this criterion (VCEP member-provided data, PP4_Moderate). A second reported patient met the phenotype point threshold as well (PMID: 9501220). A third reported patient with the same genotype exhibited similar phenotypes, but it is not clear whether the patients from PMID: 9501220 and PMID: 27375040 are distinct.
• PM3_Strong: At least two patients meeting the minimum phenotype requirement harbor the p.Val473Asp variant in the homozygous state (PMID: 9501220, SCV001430890.1, 1 pt). An additional report of a homozygous patient is found in PMID: 27375040 and PMID: 19854499, but it is not clear that this patient is unrelated to the first. A compound heterozygous patient has been described (VCEP member-provided data) harboring the variant in trans with the p.Pro363Thr variant, which has been previously classified as Likely Pathogenic by the ClinGen Leber congenital amaurosis / early-onset retinal dystrophy VCEP (1 pt, PM3_Strong).
• PP3_Moderate: The meta-predictor REVEL gives a score of 0.992, which is above the ClinGen LCA/eoRP VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The computational splicing predictor SpliceAI indicates that the variant may impact splicing by disrupting a splice acceptor (change score 0.10) or triggering a splice donor gain (change score 0.08), although these are not high-confidence predictions.

Not Met criteria codes

• BS1: This variant is absent from gnomAD v2.1.1.
• BA1: This variant is absent from gnomAD v2.1.1.

Approved on: 2024-01-31

Published on: 2024-01-31