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.1282_1303del (p.Gly428fs)

CA2580063208

2131688 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0433a93d-b9a8-48b4-9737-feab965e1d6f

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.1282_1303del

NM_000329.3(RPE65):c.1282_1303del (p.Gly428fs)

NC_000001.11:g.68431319_68431340del

CM000663.2:g.68431319_68431340del

NC_000001.10:g.68897002_68897023del

CM000663.1:g.68897002_68897023del

NC_000001.9:g.68669590_68669611del

NG_008472.1:g.23622_23643del

NG_008472.2:g.23622_23643del

ENST00000262340.6:c.1282_1303del

ENST00000262340.5:c.1282_1303del

NM_000329.2:c.1282_1303del

Likely Pathogenic

PM2_Supporting PVS1

PM3

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

NM_000329.3(RPE65):c.1282_1303del (p.Gly428MetfsTer5) is a frameshift variant that introduces a premature stop codon into exon 12 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state with the NM_000329.3(RPE65):c.1078G>C (p.Ala360Pro) variant confirmed in trans (PMID: 19431183). However, the proband was not counted for PM3 in order to avoid circularity. 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: PVS1 and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

PM2_Supporting

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

PVS1

This is a frameshift variant that introduces a premature stop codon into exon 12 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1).

PM3

This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 19431183). However, the proband was not counted for this criterion in order to avoid circularity.

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