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.1380G>A (p.Trp460Ter)

CA340742114

870343 (ClinVar)

Gene: RPE65
Condition: RPE65-related recessive retinopathy
Inheritance Mode: Autosomal recessive inheritance
UUID: fcaac434-0096-4c19-9ab9-be5edaec35c1
Approved on: 2024-02-20
Published on: 2024-02-20

HGVS expressions

NM_000329.3:c.1380G>A
NM_000329.3(RPE65):c.1380G>A (p.Trp460Ter)
NC_000001.11:g.68431135C>T
CM000663.2:g.68431135C>T
NC_000001.10:g.68896818C>T
CM000663.1:g.68896818C>T
NC_000001.9:g.68669406C>T
NG_008472.1:g.23825G>A
NG_008472.2:g.23825G>A
ENST00000262340.6:c.1380G>A
ENST00000262340.5:c.1380G>A
NM_000329.2:c.1380G>A
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Pathogenic

Met criteria codes 4
PM3 PP4 PM2_Supporting PVS1

Evidence Links 0

Expert Panel

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.1380G>A (p.Trp460Ter) is a nonsense variant that introduces a premature stop codon into exon 13 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 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.11+5G>A variant suspected in trans (0.5 points, PMID: 19117922) or the c.886del (p.Arg296fs) variant confirmed in trans (1 point, PMID: 33952291), both of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), infantile onset (1 pt), nystagmus (1 pt), no detectable rod ERG responses (0.5 pts), reduced cone ERG responses (1 pt), reduced visual acuity (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5.5 total points, PMID: 19117922, PP4). 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, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Met criteria codes
PM3
Jacobsen et al. (PMID 19117922) reports P25 who is compound heterozygous with c.11+5G>A (classified as Pathogenic by the LCA/eoRD VCEP), trans phase not confirmed (0.5 pt). Gao et al. (PMID 33952291) reports F15-1 who is compound heterozygous for the paternal c.1380G>A (p.Arg460Ter) and maternal c.886del (classified as Pathogenic by the LCA/eoRD VCEP)(1 pt). In summary 1.5 points total meets PM3.
PP4
At least one LCA patient (P25 in PMID: 19117922) with this variant displayed no detectable rod ERGs and only reduced cone ERGs, nystagmus from infancy, Visual Acuity (RE-LE) 20/1600–20/800, vessel attenuation, RPE depigmentation and granularity in the fundus which together are highly specific for RPE65 retinopathy (PP4).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PVS1
The c.1380G>A (p.Trp460Ter) variant in RPE65 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 13/14 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
Curation History
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