The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000329.3:c.1253T>A

CA340742683

Gene: RPE65
Condition: RPE65-related recessive retinopathy
Inheritance Mode: Autosomal recessive inheritance
UUID: 9c6d7eb6-1401-4787-9ebb-3021d1be6a14
Approved on: 2024-04-22
Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.1253T>A
NC_000001.11:g.68431367A>T
CM000663.2:g.68431367A>T
NC_000001.10:g.68897050A>T
CM000663.1:g.68897050A>T
NC_000001.9:g.68669638A>T
NG_008472.1:g.23593T>A
NG_008472.2:g.23593T>A
ENST00000262340.6:c.1253T>A
ENST00000262340.5:c.1253T>A
NM_000329.2:c.1253T>A
More

Likely Pathogenic

Met criteria codes 5
PS3_Supporting PP3_Moderate PP4 PM3 PM2_Supporting

Evidence Links 0

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP
NM_000329.3(RPE65):c.1253T>A is a missense variant predicted to replace phenylalanine with tyrosine at position 418. This variant is absent from gnomAD v2.1.1 (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.997G>C (p.Gly333Arg) variant confirmed in trans, which was previously classified as likely pathogenic by the ClinGen LCA / eoRD VCEP (1 point, PMID: 34830511, PM3). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pt), symptomatic onset between birth and age five years (1 pt), decreased central visual acuity (1 pt), nystagmus (1 pt), macular dystrophy (0.5 pt), and absent ERG responses from rods (0.5 pt) and cones (1 pt), which together are specific for RPE65-related recessive retinopathy (5.5 points, PMID: 34830511, PP4). The computational predictor REVEL gives a score of 0.895, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 22745121). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Met criteria codes
PS3_Supporting
The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 22745121).
PP3_Moderate
The computational predictor REVEL gives a score of 0.895, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).
PP4
At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pt), symptomatic onset between birth and age five years (1 pt), decreased central visual acuity (1 pt), nystagmus (1 pt), macular dystrophy (0.5 pt), and absent ERG responses (0.5 pt) which together are specific for RPE65-related recessive retinopathy (4.5 points, PMID: 34830511, PP4).
PM3
This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.997G>C (p.Gly333Arg) variant confirmed in trans (1 point, PMID: 34830511) which was previously classified as likely pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PM3).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
Curation History
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