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]

Variant: NM_000329.3(RPE65):c.444_445del (p.Glu148fs)

CA1173563400

973966 (ClinVar)

Gene: RPE65 (HGNC:6121)

Condition: RPE65-related recessive retinopathy (MONDO:0100368)

Inheritance Mode: Autosomal recessive inheritance

UUID: 2a23c55c-4afc-4e98-96e0-8ef8e09266e7

Approved on: 2025-06-30

Published on: 2025-06-30

HGVS expressions

NM_000329.3(RPE65):c.444_445del (p.Glu148fs)

NM_000329.3:c.444_445del

NC_000001.11:g.68444584_68444585del

CM000663.2:g.68444584_68444585del

NC_000001.10:g.68910267_68910268del

CM000663.1:g.68910267_68910268del

NC_000001.9:g.68682855_68682856del

NG_008472.1:g.10378_10379del

NG_008472.2:g.10378_10379del

ENST00000262340.6:c.444_445del

ENST00000262340.5:c.444_445del

NM_000329.2:c.444_445del

Pathogenic

PVS1 PM2_Supporting 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.444_445del (p.Glu148AspfsTer8) is a frameshift variant that introduces a premature stop codon into exon 5 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 v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant confirmed in trans, which was previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (1 point, VCEP member-provided data, PM3). 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, PM2_Supporting, and PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

PVS1

This is a frameshift variant that introduces a premature stop codon into exon 5 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).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PM3

This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant confirmed in trans, which was previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (1 point, VCEP member-provided data, PM3).

Curation History

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