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]

Variant: NM_000329.3(RPE65):c.1056G>A (p.Glu352=)

CA285811

98820 (ClinVar)

Gene: RPE65
Condition: RPE65-related recessive retinopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 3c959bf6-5aa6-41da-be36-f55c9b5b5fe0
Approved on: 2023-12-22
Published on: 2023-12-22

HGVS expressions

NM_000329.3:c.1056G>A
NM_000329.3(RPE65):c.1056G>A (p.Glu352=)
NC_000001.11:g.68438259C>T
CM000663.2:g.68438259C>T
NC_000001.10:g.68903942C>T
CM000663.1:g.68903942C>T
NC_000001.9:g.68676530C>T
NG_008472.1:g.16701G>A
NG_008472.2:g.16701G>A
ENST00000262340.6:c.1056G>A
ENST00000262340.5:c.1056G>A
NM_000329.2:c.1056G>A
More

Benign

Met criteria codes 1
BA1
Not Met criteria codes 2
BP4 BP7

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
The NM_000329.3:c.1056G>A variant is a synonymous variant in codon 352 of RPE65, and is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.3944, with 8033 alleles / 19884 total alleles in the East Asian population with 1627 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant does not have a strong prediction of impact at splicing sites according to SpliceAI, which calculates a delta score of 0.12 for splice acceptor gain. Because this score is higher than the ClinGen LCA / eoRD VCEP BP4 / BP7 threshold of <0.1 and lower than the PP3 threshold of >0.2, no in silico predictive codes are met. 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. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Met criteria codes
BA1
This variant is present in gnomAD v.2.1.1 at a PopMax allele frequency of 0.3944, with 8033 alleles / 19884 total alleles in the East Asian population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008. Additionally, there are 1627 homozygotes in the East Asian population (BA1).
Not Met criteria codes
BP4
This silent variant c.1056G>A causing a synonymous variant at codon 352 does not have a strong prediction of impact at splicing sites according to Splice AI, which predicts a delta score of 0.00 for acceptor loss, 0.12 at 57bp for acceptor gain, 0.08 at -72bp for donor gain, and 0.00 for donor loss. Because one of these scores is higher than the ClinGen LCA / eoRD VCEP threshold of <0.1, BP4 and BP7 are not met.
BP7
This silent variant c.1056G>A causing a synonymous variant at codon 352 does not have a strong prediction of impact at splicing sites according to Splice AI, which predicts a delta score of 0.00 for acceptor loss, 0.12 at 57bp for acceptor gain, 0.08 at -72bp for donor gain, and 0.00 for donor loss. Because one of these scores is higher than the ClinGen LCA / eoRD VCEP threshold of <0.1, BP4 and BP7 are not met.
Curation History
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