Variant: NM_000329.3(RPE65):c.1302G>A (p.Ala434=)

CA902209

467825 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: f317b16a-76d9-4d00-b945-62323da833e7

HGVS expressions

NM_000329.3:c.1302G>A
NM_000329.3(RPE65):c.1302G>A (p.Ala434=)
NC_000001.11:g.68431318C>T
CM000663.2:g.68431318C>T
NC_000001.10:g.68897001C>T
CM000663.1:g.68897001C>T
NC_000001.9:g.68669589C>T
NG_008472.1:g.23642G>A
NG_008472.2:g.23642G>A
ENST00000262340.6:c.1302G>A
ENST00000262340.5:c.1302G>A
NM_000329.2:c.1302G>A

Benign

• Met criteria codes: BP7 BP4 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.1302G>A (p.Ala434=) is a synonymous variant that is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.02695, with 734 alleles / 24954 total alleles and 7 homozygotes in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.07 for donor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• BP7: This silent variant, c.1302G>A, causing a synonymous variant at codon 434 does not have an impact at splicing sites according to SpliceAI, which predicts a delta score of 0.07 for donor loss which is below the ClinGen LCA / eoRD VCEP threshold of <0.1 (BP7).
• BP4: There is no computational predictor REVEL score for the variant NM_000329.3(RPE65):c.1302G>A (p.Ala434=). However, the splicing impact predictor SpliceAI gives a delta score of 0.07 for donor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4).
• BA1: This variant is present in gnomAD v.2.1.1 at a PopMax allele frequency of 0.02695, with 734 alleles / 24954 total alleles and 7 homozygotes in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1).

Approved on: 2023-12-22

Published on: 2023-12-22