ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.89dup (p.Thr31fs)

dbSNP: rs281865286
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Total submissions: 4
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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 RCV003764798 SCV004697403 pathogenic RPE65-related recessive retinopathy 2024-02-20 reviewed by expert panel curation NM_000329.3(RPE65):c.89dup (p.Thr31fs) is a frameshift variant that introduces a premature stop codon into exon 2 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). At least one proband harboring this variant exhibits a phenotype including diagnosis of cone-rod dystrophy, nyctalopia, RPE mottling (0.5 pts), abnormal color vision (1 pt), absence of fundus autofluorescence (2 pts), and infantile onset (1 pt), which together are specific for RPE65-related recessive retinopathy (4.5 total pts, PMID: 17525851, PMID: 15288992, 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 and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376508 SCV001573682 likely pathogenic Retinitis pigmentosa 20 2021-04-08 criteria provided, single submitter research The RPE65 c.89dup variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic.
Invitae RCV002514527 SCV003523307 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2023-08-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr31Asnfs*21) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 9326941). This variant is also known as ins144T. ClinVar contains an entry for this variant (Variation ID: 98898). For these reasons, this variant has been classified as Pathogenic.
Retina International RCV000085230 SCV000117367 not provided not provided no assertion provided not provided

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