Evidence Repository - Clinical Genome Resources

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.644-42del

CA226572

98885 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: af9d4f7c-1a61-4f29-87e1-03742b7473ca

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.644-42del

NM_000329.3(RPE65):c.644-42del

NC_000001.11:g.68439684del

CM000663.2:g.68439684del

NC_000001.10:g.68905367del

CM000663.1:g.68905367del

NC_000001.9:g.68677955del

NG_008472.1:g.15276del

NG_008472.2:g.15276del

ENST00000262340.6:c.644-42del

ENST00000262340.5:c.644-42del

NM_000329.2:c.644-42del

Likely Benign

BP7 BP4 BS1

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

The c.644-42del variant in RPE65, is an intronic variant which is present outside of consensus splice sites. The splicing impact predictor SpliceAI gives a delta score of 0.09, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In addition, the PhyloP score was -2.63 which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1, which depicts that the nucleotide is not highly conserved. This intronic variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.000827, with 26/24712 in the African/ African-American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). In summary this variant meets criteria to be classified as Likely Benign for Leber congenital amaurosis (RPE65) based on the ACMG/AMP criteria (codes met: BP4, BP7, BS1). (VCEP specifications version 1.0.0; date of approval 09/21/2023).

BP7

This intronic variant [c.644-42del] does not have an impact at splicing sites according to SpliceAI, which predicts a delta score of [0.09] for acceptor loss, which is below the ClinGen LCA / eoRD VCEP threshold of <0.1. (BP7)

BP4

The splicing impact predictor SpliceAI gives a delta score of 0.09, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4).

BS1

The NM_000329.3(RPE65):c.644-42del intronic variant is present in gnomAD v.2.1.1 at a PopMax allele frequency of 0.008271, with 26/24712 in the African/ African-American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1).

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