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.361dup (p.Ser121fs)

CA23575009

559521 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 84b2275b-ad74-4589-ba40-0345b89e8231

HGVS expressions

NM_000329.3:c.361dup

NM_000329.3(RPE65):c.361dup (p.Ser121fs)

NC_000001.11:g.68444671dup

CM000663.2:g.68444671dup

NC_000001.10:g.68910354dup

CM000663.1:g.68910354dup

NC_000001.9:g.68682942dup

NG_008472.1:g.10295dup

NG_008472.2:g.10295dup

ENST00000262340.6:c.361dup

ENST00000262340.5:c.361dup

NM_000329.2:c.361dup

Pathogenic

PVS1 PP4_Moderate 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

The NM_000329.3(RPE65):c.361dup (p.Ser121fs) frameshift variant introduces a premature stop codon in exon 5 of 14 and is predicted to trigger nonsense-mediated decay (PVS1). It is reported in the literature in a compound heterozygous state in at least one proband (by whole exome sequencing) who was diagnosed with Leber congenital amaurosis and exhibits infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), flat rod ERG (required, 1 pt), and flat cone ERG (1 pt), which together is highly specific for RPE65-related recessive retinopathy (PMID: 30870047, PP4_Moderate). 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, PP4_Moderate, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023)

PVS1

This variant causes a frameshift in exon 5 of 14 and is predicted to trigger nonsense-mediated decay (PVS1).

PP4_Moderate

Proband RPCR-XVI-1 from PMID: 30870047 has been found by whole exome (2 pt) to harbor this paternal variant in compound heterozygous state with the maternal p.Arg446Ser variant and has been diagnosed with LCA including infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), flat rod ERG (required, 1 pt), and flat cone ERG (1 pt), which together is highly specific for RPE65-related recessive retinopathy (PP4_Moderate).

PM2_Supporting

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

PM3

Proband RPCR-XVI-1 is diagnosed with LCA and harbors a paternal c.361dup (p.Ser121Phefs*10 variant and maternal p.Arg446Ser variant, but has not been considered for this criterion in order to avoid circularity.

Approved on: 2024-02-20

Published on: 2024-02-20

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