ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.95-2A>T

gnomAD frequency: 0.00001  dbSNP: rs61751279
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Total submissions: 13
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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 RCV003460771 SCV004190223 pathogenic RPE65-related recessive retinopathy 2023-12-22 reviewed by expert panel curation The NM_000329.3(RPE65):c.95-2A>T variant disrupts a canonical splice site in intron 2 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). At least 6 probands have been reported with this variant, one of whom displayed markedly impaired night vision (0.5 pts), reduced visual acuity 20/60 from an early age (1 pt), nystagmus (1 pt), RPE demelanization (0.5 pts), poor pupillary light response (0.5 pts), significant outer nuclear layer preservation for the severity of visual loss (1 pt), nondetectable ERG responses from rods (0.5 pts) and cones (1 pt), and minimal autofluorescence (2 pts), which together are highly specific for RPE65 retinopathy (8 pts total, PP4_Moderate, PMID: 20604683). The proband's affected sibling II:2 is also homozygous for this variant (PP1). At least 3 probands with the required phenotype of extinguished ERG harbor the variant in the homozygous state (1 point, PMID: 20604683, PMID: 17724218, PMID: 15024725, PM3). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002298, with 3 alleles / 34592 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, PM3, and PP1. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Counsyl RCV000668398 SCV000792991 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2017-07-25 criteria provided, single submitter clinical testing
Invitae RCV000668398 SCV001219454 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2023-12-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 of the RPE65 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 9843205, 18632300). This variant is present in population databases (rs61751279, gnomAD 0.009%). Disruption of this splice site has been observed in individuals with RPE65-related conditions (PMID: 15024725, 17724218, 21151602). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98899). 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.
Blueprint Genetics RCV001074560 SCV001240151 pathogenic Retinal dystrophy 2018-12-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002498451 SCV002811556 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement 2021-10-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001003189 SCV003800727 pathogenic Leber congenital amaurosis 2023-01-19 criteria provided, single submitter clinical testing Variant summary: RPE65 c.95-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3 prime acceptor site; four predict the variant creates a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 251428 control chromosomes. c.95-2A>T has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis. These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000085232 SCV004032956 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing RPE65: PVS1, PM2, PM3
Baylor Genetics RCV001250674 SCV004209248 pathogenic Leber congenital amaurosis 2 2023-08-08 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000085232 SCV004238122 pathogenic not provided 2023-06-13 criteria provided, single submitter clinical testing
Retina International RCV000085232 SCV000117369 not provided not provided no assertion provided not provided
Sharon lab, Hadassah-Hebrew University Medical Center RCV001003189 SCV001161266 pathogenic Leber congenital amaurosis 2019-06-23 no assertion criteria provided research
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV001250674 SCV001425544 pathogenic Leber congenital amaurosis 2 no assertion criteria provided research
Natera, Inc. RCV001003189 SCV001460415 pathogenic Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing

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