Evidence Repository
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(RPE65):c.1301C>A (p.Ala434Glu)

CA340742486

850613 (ClinVar)

Gene: RPE65
Condition: RPE65-related recessive retinopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 8da3ac20-f2f0-43e1-b08a-6d3d7773bda9
Approved on: 2024-04-22
Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.1301C>A
NM_000329.3(RPE65):c.1301C>A (p.Ala434Glu)
NC_000001.11:g.68431319G>T
CM000663.2:g.68431319G>T
NC_000001.10:g.68897002G>T
CM000663.1:g.68897002G>T
NC_000001.9:g.68669590G>T
NG_008472.1:g.23641C>A
NG_008472.2:g.23641C>A
ENST00000262340.6:c.1301C>A
ENST00000262340.5:c.1301C>A
NM_000329.2:c.1301C>A

Likely Pathogenic

Met criteria codes 5
PM2_Supporting PM3_Strong PP3 PP1 PP4

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.1301C>A is a missense variant encoding a substitution of alanine by glutamic acid at codon 434. This variant is present in gnomAD v.4.0.0 at a frequency of 0.0000008994, with 1/1111886 alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In the Middle Eastern genetic ancestry group, the frequency of 1/5768 alleles (0.0001734) is also lower than the PM2_Supporting threshold. This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.1399C>G (p.Pro467Ala) variant confirmed in trans (1 pt, PMID: 31273949), the NM_000329.3(RPE65):c.95-2A>T variant suspected in trans (0.5 pts, LOVD), or the NM_000329.3(RPE65):c.74C>T (p.Pro25Leu) variant suspected in trans (0.5 pts, PMID: 29033008) all of which were previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 31273949, PP1). The computational predictor REVEL gives a score of 0.769, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3). At least one proband harboring this variant exhibits a phenotype including extinguished rod ERG responses (0.5 pts), fundus albipunctatus / white dots (2 pts), onset between birth and age 5 years (1 pt), evidence of cone involvement on ERG (1 pt), and night blindness (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5 pts, PMID: 31273949, PP4). 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_Strong, PP1, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Met criteria codes
PM2_Supporting
This variant is present in gnomAD v.4.0.0 at a frequency of 8.994e-7, with 1/ 1111886 alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In the Middle Eastern genetic ancestry group, the frequency of 1/5768 alleles (0.0001734) is also lower than the threshold.
PM3_Strong
This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy. One proband (PMID:31273949) is compound heterozygous (confirmed in trans) with the c.1399C>G; p.Pro467Ala variant, previously curated as Pathogenic by the LCA/eoRD VCEP (1 point). A second proband is reported in the LOVD database to be found with the c.95-2A>T variant, previously curated as Pathogenic by the LCA/eoRD VCEP. No confirmation of phase available. (0.5 points). A third proband is reported (PMID:29033008) found with p.Pro25Leu variant which does not have confirmation of phase but has been classified by the LCA/eoRD VCEP as Pathogenic (0.5 points) 2.0 total points, PM3_Strong.
PP3
The computational predictor REVEL gives a score of 0.769, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.644 for PP3_Supporting and predicts a damaging effect on RPE65 function (PP3). The LCA/eoRD VCEP threshold for PP3_Moderate is 0.774 and is almost met. AlphaMissense analysis of the variant predicts "likely pathogenic" with a score of 0.9732.
PP1
The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 31273949).
PP4
Individual P01-II:2 had extinguished rod ERG responses (0.5 pts), fundus albipunctatus/white dots (2 pts), onset between birth and age 5 (1 pt), evidence of cone involvement on ERG (1 pt), and night blindness (0.5 pts) which together are specific for RPE65-related recessive retinopathy (5.0 points, PMID: 31273949, PP4).
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