ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.11+5G>A

gnomAD frequency: 0.00014  dbSNP: rs61751276
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Total submissions: 21
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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 RCV003460766 SCV004190222 pathogenic RPE65-related recessive retinopathy 2023-12-22 reviewed by expert panel curation The NM_000329.3(RPE65):c.11+5G>A variant is a putative splicing variant in intron 1 of the RPE65 gene. The computational splicing predictor SpliceAI lists a change score of 0.58 for splice donor gain, predicting a deleterious impact on splicing (PP3). VCEP-member provided data from a mini-gene assay in HEK-293 cells show that this variant reduces normal splicing and leads to >400x reduction of mature mRNA, relative to the wild-type control (PS3_Supporting, Guan et al., 2024). At least 3 patients with this variant have been reported with detailed phenotypes (PMID: 21211845, PMID: 11786058), one of whom exhibited nonrecordable ERG responses from rods (0.5 pts) and cones (1 pt), congenital night blindness (0.5 pts), absence of autofluorescence (2 pts), optic nerve pallor (0.5 pts), RPE granularity (0.5 pts), onset between birth and age 5 years (1 pt), OCT preserved at macula (1 pt), constricted Goldmann visual field (1 pt), decreased central visual acuity (1 pt), and nystagmus (1 pt), which together are highly specific for recessive RPE65 retinopathy (10 pts total, VCEP member-provided data, PP4_Moderate). This variant has been detected in at least 7 published cases with recessive retinopathy, including at least two individuals homozygous for the variant (1 pt) and three individuals compound heterozygous for this variant in trans with either the c.615_616del (p.Ile206Cysfs*27), p.Glu102Ter, or c.89dup (p.Thr31fs) variant, all which have been classified Pathogenic by this VCEP (4pts, PMID: 11095629, PMID: 17525851, PMID: 35129589), (PM3_Very-Strong). Two publications contain segregation data (PMID: 11786058 and PMID: 35001204), with one set of genotype-positive siblings exhibiting the required phenotype of absent or severely decreased rod electroretinogram response (PP1). The GrpMax Filtering AF for this variant in gnomAD v2.1.1 is 0.0001017 (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: PM3_Very-Strong, PP4_Moderate, PP1, PM2_Supporting, PP3, PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Eurofins Ntd Llc (ga) RCV000085149 SCV000336650 pathogenic not provided 2015-10-29 criteria provided, single submitter clinical testing
Invitae RCV000524808 SCV000644178 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2024-01-04 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the RPE65 gene. It does not directly change the encoded amino acid sequence of the RPE65 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs61751276, gnomAD 0.02%). This variant has been observed in individual(s) with retinitis pigmentosa or Leber congenital amaurosis (PMID: 9326941, 11462243, 11786058, 19854499, 20683928, 21211845, 25257057). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 65+5G>A and IVS1+5G>A. ClinVar contains an entry for this variant (Variation ID: 98825). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 RCV000505050 SCV001239587 pathogenic Retinal dystrophy 2018-10-19 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000085149 SCV001245624 pathogenic not provided 2023-12-01 criteria provided, single submitter clinical testing RPE65: PM3:Very Strong, PM2, PS3:Moderate
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000678614 SCV001370364 likely pathogenic Retinitis pigmentosa 20 2019-06-12 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000085149 SCV001446854 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV000678614 SCV001573683 pathogenic Retinitis pigmentosa 20 2021-04-08 criteria provided, single submitter research The RPE65 c.11+5G>A 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, PM3, PP1-S, PP3, PM1. Based on this evidence we have classified this variant as Pathogenic.
Revvity Omics, Revvity RCV000085149 SCV002019070 likely pathogenic not provided 2021-06-12 criteria provided, single submitter clinical testing
GeneDx RCV000085149 SCV002513583 pathogenic not provided 2023-01-12 criteria provided, single submitter clinical testing Published functional studies suggest that the variant causes a defect in RPE65 expression (Vazquez-Dominguez et al., 2022); This variant is associated with the following publications: (PMID: 11462243, 20683928, 23891399, 17964524, 32531858, 11786058, 19854499, 9326941, 20079931, 10766140, 25257057, 17525851, 21211845, 20811047, 18441370, 30268864, 31174678, 31736247, 32581362, 32865313, 12960219, 35121194, 34492281, 35129589, 34906171, 36429068, 29332120)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001275342 SCV002572262 pathogenic Leber congenital amaurosis 2022-08-23 criteria provided, single submitter clinical testing Variant summary: RPE65 c.11+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.6e-05 in 251324 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RPE65 causing Leber Congenital Amaurosis (7.6e-05 vs 0.0014), allowing no conclusion about variant significance. c.11+5G>A has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis/Visual impairment/Retinopathies (example, Galvin_2005, Astuti_2016, Haer-Wigman_2017, Testa_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002498448 SCV002811140 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement 2022-03-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000085149 SCV003800439 pathogenic not provided 2022-10-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV000022752 SCV004209224 pathogenic Leber congenital amaurosis 2 2023-10-05 criteria provided, single submitter clinical testing
OMIM RCV000678614 SCV000044040 pathogenic Retinitis pigmentosa 20 2003-09-01 no assertion criteria provided literature only
OMIM RCV000022752 SCV000044041 pathogenic Leber congenital amaurosis 2 2003-09-01 no assertion criteria provided literature only
Retina International RCV000085149 SCV000117286 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505050 SCV000598728 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000678614 SCV000804701 likely pathogenic Retinitis pigmentosa 20 2016-09-01 no assertion criteria provided clinical testing
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV000022752 SCV001425541 pathogenic Leber congenital amaurosis 2 no assertion criteria provided research
Natera, Inc. RCV001275342 SCV001460417 pathogenic Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing

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