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.1067del (p.Asn356fs)

CA226477

98821 (ClinVar)

Gene: RPE65
Condition: RPE65-related recessive retinopathy
Inheritance Mode: Autosomal recessive inheritance
UUID: daeb1902-db11-4ce0-a723-fc1f96265b49
Approved on: 2024-04-22
Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.1067delA
NM_000329.3:c.1067del
NM_000329.3(RPE65):c.1067del (p.Asn356fs)
NC_000001.11:g.68438255del
CM000663.2:g.68438255del
NC_000001.10:g.68903938del
CM000663.1:g.68903938del
NC_000001.9:g.68676526del
NG_008472.1:g.16712del
NG_008472.2:g.16712del
ENST00000262340.6:c.1067del
ENST00000262340.5:c.1067del
NM_000329.2:c.1067del
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Pathogenic

Met criteria codes 4
PVS1 PM3_Strong PP4 PM2_Supporting

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.1067del (p.Asn356MetfsTer17) is a frameshift variant that introduces a premature stop codon into exon 10 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 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) or NM_000329.3(RPE65):c.11+5G>A variants confirmed in trans (2 points, PMID: 9326927, PMID: 37704110), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including a clinical diagnosis of Leber congenital amaurosis (0.5 pts), nystagmus (1 pt), decreased peripheral vision (1 pt), absent or severely decreased rod electroretinogram (ERG) responses (0.5 pts) and abnormal color vision or evidence of cone involvement on ERG (1 pt), which together are specific for RPE65-related recessive retinopathy (4 pts, PMID: 31273949, 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_Strong and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Met criteria codes
PVS1
This is a frameshift variant that introduces a premature stop codon into exon 10 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_Strong
This variant has been reported in at least 2 probands with Leber congenital amaurosis who were compound heterozygous with the c.700C>T (p.Arg234Ter) and c.11+5G>A variants confirmed in trans (2 points, PMIDs: 9326927, 37704110), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong).
PP4
At least one proband harboring this variant exhibits a phenotype including Clinical diagnosis of Leber congenital amaurosis (0.5), Nystagmus (1), Decreased peripheral vision (1), Absent or severely decreased rod electroretinogram (ERG) responses (0.5) and Abnormal color vision or evidence of cone involvement on ERG (1), which together are specific for RPE65-related recessive retinopathy (4 points, PP4) (PMID: 31273949).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
Curation History
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