Evidence Repository
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:c.1336dup

CA2580612187

Gene: RPE65
Condition: RPE65-related recessive retinopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: dbf33565-7a95-454a-ac2e-ba2c69e94c15
Approved on: 2024-02-20
Published on: 2024-02-20

HGVS expressions

NM_000329.3:c.1336dup
NC_000001.11:g.68431284dup
CM000663.2:g.68431284dup
NC_000001.10:g.68896967dup
CM000663.1:g.68896967dup
NC_000001.9:g.68669555dup
NG_008472.1:g.23676dup
NG_008472.2:g.23676dup
ENST00000262340.6:c.1336dup
ENST00000262340.5:c.1336dup
NM_000329.2:c.1336dup

Pathogenic

Met criteria codes 3
PVS1 PM2_Supporting PM3
Not Met criteria codes 20
BS4 BS3 BS1 BP5 BP7 BP3 BP4 BP1 PM6 PS2 PS1 PS4 PS3 PM4 PM5 BA1 PP4 PP1 PP3 PP2

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.1336dup (p.Arg446LysfsTer4) is a frameshift variant that introduces a premature stop codon into exon 12 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 3 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 30268864, 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, PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Met criteria codes
PVS1
Frameshift variant predicted to undergo NMD (exon 12/14)
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PM3
Found in a homozygous state in a 32 yo hispanic woman with 7.0 total visual field hill of vision and 2.9 on central 30º Visual Field Hill of Vision. The patient was treated with recombinant adeno-associated virus vector expressing RPE65 and showed improvement in kinetic visual fields and V30 and Vtot (PMID: 27102010). Found in a homozygous state on two subjects with LCA clinical diagnosis using Visual acuity (VA), Goldmann visual field (GVF), optical coherence tomography, color vision testing, light sensitivity testing, and electroretinograms (retinal imaging and fundus photography (PMID: 30268864).
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
At least one proband harboring this variant exhibited a phenotype including reduced visual acuity (1 pt), constriction of peripheral visual field (1 pt), and severely reduced rod (0.5 pts) and cone (1 pt) ERG responses (3.5 pts total, PMID: 27102010). Although the proband participated in a gene therapy trial as an adult, subsequent results were difficult to interpet, so PP4 was not met.
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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