ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.700C>T (p.Arg234Ter)

gnomAD frequency: 0.00001  dbSNP: rs61752895
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Total submissions: 9
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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 RCV003460467 SCV004190226 pathogenic RPE65-related recessive retinopathy 2023-12-22 reviewed by expert panel curation NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) is a nonsense variant that introduces a premature stop codon in exon 7 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 6 probands have been reported with this variant, one of whom displayed nystagmus (1 pt), night blindness (0.5 pts), reduced visual acuity (1 pt), narrowing of retinal vessels (0.5 pts), moderate pallor of the optic discs (0.5 pts), difficulty discriminating any color (1 pt), unrecordable ERG (0.5 pts), absent autofluorescence (2 pts), and onset at birth (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total pts, PMIDs: 9326927, PMID: 11264131 PMID: 15288992, PP4_moderate). Additionally, the variant has been reported to segregate with the phenotype (confirmed by absent ERG) in the proband plus one similarly affected sibling harboring the variant in the compound heterozygous state (PP1; PMID: 9326927). PM3 was not considered to avoid circularity, despite the presence of compound heterozygous cases harboring this variant as well as the p.Asn356fs, c.991_993dup (p.Trp331dup), or p.Arg124Ter variant. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002299, with 3 alleles / 34580 total alleles in the Admixed 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, PM2_Supporting, and PP1. (VCEP specifications version 1.0.0; date of approval 09/21/2023)
Labcorp Genetics (formerly Invitae), Labcorp RCV001236263 SCV001408979 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2024-07-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg234*) 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 (rs61752895, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with inherited retinal dystrophy (PMID: 9326927, 30268864). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13114). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376448 SCV001573589 pathogenic Retinitis pigmentosa 20 2021-04-08 criteria provided, single submitter research The RPE65 c.700C>T 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: PP1-M, PM2, PVS1. Based on this evidence we have classified this variant as Pathogenic.
Baylor Genetics RCV000013993 SCV004209274 pathogenic Leber congenital amaurosis 2 2024-03-25 criteria provided, single submitter clinical testing
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel RCV004794340 SCV005415432 pathogenic Retinal dystrophy 2024-05-27 criteria provided, single submitter research
OMIM RCV000013993 SCV000034240 pathogenic Leber congenital amaurosis 2 1997-10-01 no assertion criteria provided literature only
Retina International RCV000085219 SCV000117356 not provided not provided no assertion provided not provided
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV000013993 SCV001425558 pathogenic Leber congenital amaurosis 2 no assertion criteria provided research
Natera, Inc. RCV001831567 SCV002092763 pathogenic Leber congenital amaurosis 2020-03-20 no assertion criteria provided clinical testing

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