ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.1205G>A (p.Trp402Ter)

gnomAD frequency: 0.00009  dbSNP: rs774130993
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen RCV003461248 SCV004190224 pathogenic RPE65-related recessive retinopathy 2023-12-22 reviewed by expert panel curation This is a nonsense variant that introduces a premature stop codon into exon 11 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). At least one patient was analyzed on a 100+ retinal dystrophy gene panel testing that did not provide an alternative explanation for visual impairment (2 pts), displayed non-detectable ERG responses from rods (0.5 pts) and cones (1 pt), visual acuity 20/400 (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (0.5 pts), and no pigment in peripheral retina (0.5 pts), which together are specific for RPE65 retinopathy (7.5 pts total, PMID: 23847139, PP4). This variant has also been reported in at least 8 probands, one of whom exhibited LCA and was compound heterozygous with the p.Leu341Ser suspected in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PMID: 23847139, PM3_Supporting). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00008316, with 9 alleles / 24960 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). 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, PM3_Supporting, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/23/2023).
Invitae RCV000817537 SCV000958103 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2023-12-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp402*) in the RPE65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 9843205, 18632300). This variant is present in population databases (rs774130993, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 17964524). ClinVar contains an entry for this variant (Variation ID: 660359). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075233 SCV001240847 pathogenic Retinal dystrophy 2017-03-27 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV001089892 SCV001245399 likely pathogenic Leber congenital amaurosis 2 2020-02-14 criteria provided, single submitter curation This variant is interpreted as likely pathogenic for Leber congenital amaurosis 2, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PVS1-Strong.
GeneDx RCV001593012 SCV001817000 pathogenic not provided 2023-08-09 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23847139, 37521805, 25525159, 17964524, 32865313, 34492281, 31925606)
Baylor Genetics RCV001089892 SCV004209249 pathogenic Leber congenital amaurosis 2 2023-08-04 criteria provided, single submitter clinical testing
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV001089892 SCV001425583 pathogenic Leber congenital amaurosis 2 no assertion criteria provided research
Natera, Inc. RCV001830793 SCV002092742 pathogenic Leber congenital amaurosis 2020-10-15 no assertion criteria provided clinical testing

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