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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000329.3(RPE65):c.495+1dup

CA226556

98872 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f294a8ca-4abf-45e7-9efb-1db647385330

Approved on: 2023-12-22

Published on: 2023-12-22

HGVS expressions

NM_000329.3:c.495+1dup

NM_000329.3(RPE65):c.495+1dup

NC_000001.11:g.68444531dup

CM000663.2:g.68444531dup

NC_000001.10:g.68910214dup

CM000663.1:g.68910214dup

NC_000001.9:g.68682802dup

NG_008472.1:g.10430dup

NG_008472.2:g.10430dup

ENST00000262340.6:c.495+1dup

ENST00000262340.5:c.495+1dup

NM_000329.2:c.495+1dup

Pathogenic

PM3 PVS1 PM2_Supporting

PS3 PS1 BA1 PP4 PP3 PP2 PM1 PM4 PM5 BS3 BS1 BS2 BP7 BP3 BP4 BP1

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 NM_000329.3(RPE65): c.495+1dup variant disrupts a canonical splice site in intron 5 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 point, PMID: 26656277). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy, one of whom was compound heterozygous with the c.130C>T p.Arg44Ter variant confirmed in trans (1 pt, PMID: 26626312) which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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: PVS1, PM3_strong, PM2_supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023).

PM3

This variant has been reported in at least 1 unrelated proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 point, PMID: 26656277). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy, one of whom was compound heterozygous with the c.130C>T p.Arg44Ter variant confirmed in trans (1 points, PMID: 26626312) which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3).

PVS1

This variant disrupts a canonical splice site in intron 5 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting)

PS3

N/A

PS1

N/A

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

N/A

PP2

N/A

PM1

N/A

PM4

N/A

PM5

N/A

BS3

N/A

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS2

N/A

BP7

N/A

BP3

N/A

BP4

N/A

BP1

N/A

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