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.370C>T (p.Arg124Ter)

CA226545

98866 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 86306b55-3d7f-4eb7-885d-46f107384d83

Approved on: 2024-02-20

Published on: 2024-02-20

HGVS expressions

NM_000329.3:c.370C>T

NM_000329.3(RPE65):c.370C>T (p.Arg124Ter)

NC_000001.11:g.68444656G>A

CM000663.2:g.68444656G>A

NC_000001.10:g.68910339G>A

CM000663.1:g.68910339G>A

NC_000001.9:g.68682927G>A

NG_008472.1:g.10304C>T

NG_008472.2:g.10304C>T

ENST00000262340.6:c.370C>T

ENST00000262340.5:c.370C>T

NM_000329.2:c.370C>T

Pathogenic

PM2_Supporting PM3_Supporting PVS1

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.370C>T (p.Arg124Ter) is a nonsense 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 present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002191, with 9 alleles / 24480 total alleles in the African/African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 35129589, PM3_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, PM2_Supporting, PM3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

PM2_Supporting

This variant is present in gnomAD v.2.1.1 at a PopMax allele frequency of 0.00002191, with 9 alleles / 24480 total alleles in the African / African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). Please note that the PopMax frequency of this variant in gnomAD v4 is higher but similarly below the PM2_Supporting threshold (0.00007713, with 23 allele / 74982 total alleles in the African / African-American population).

PM3_Supporting

This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts), PMID: 35129589; PM3_Supporting). Additional probands have been reported but have not been included in PM3 to avoid circularity.

PVS1

This is a nonsense 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).

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