Variant: NM_000329.3(RPE65):c.1244C>T (p.Ala415Val)

CA16617183

421620 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: f548066b-0b8f-4134-a015-ff673e1f1743

Approved on: 2024-02-18

Published on: 2024-02-18

HGVS expressions

NM_000329.3:c.1244C>T
NM_000329.3(RPE65):c.1244C>T (p.Ala415Val)
NC_000001.11:g.68431376G>A
CM000663.2:g.68431376G>A
NC_000001.10:g.68897059G>A
CM000663.1:g.68897059G>A
NC_000001.9:g.68669647G>A
NG_008472.1:g.23584C>T
NG_008472.2:g.23584C>T
ENST00000262340.6:c.1244C>T
ENST00000262340.5:c.1244C>T
NM_000329.2:c.1244C>T

Likely Pathogenic

• Met criteria codes: PM3_Supporting PP3_Moderate 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.1244C>T is a missense variant causing substitution of alanine with valine at position 415. This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.0001638, with 1 allele / 6104 total alleles in the Remaining individuals 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 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.886dup (p.Arg296fs) variant suspected in trans (PMID: 27102010, PMID: 30268864, PMID: 37660736), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PM3_Supporting). At least one proband harboring this variant has exhibited a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), onset before age 5 years (1 pt), flat ERG responses for rods (0.5 pts) and cones (1 pt), and improvement of night vision following RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (11 total pts, PMID: 37660736, PP4_Moderate). The computational predictor REVEL gives a score of 0.775, 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 / eoRD VCEP: PM2_Supporting, PM3_Supporting, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PM3_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.886dup (p.Arg296fs) variant suspected in trans (PMID: 27102010, PMID: 30268864, PMID: 37660736), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PM3_Supporting). This variant is alternatively referred to as p.Lys294ins1gac.
• PP3_Moderate: The computational predictor REVEL gives the variant a score of 0.775, which is above the ClinGen LCA / eoRD VCEP threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).
• PM2_Supporting: This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.0001638, with 1 alleles / 6104 total alleles] in the Remaining individuals 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 has exhibited a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), onset before age 5 years (1 pt), flat ERG responses for rods (0.5 pts) and cones (1 pt), and improvement of night vision following RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (11 total pts, PMID: 37660736, PP4_Moderate).