Submissions for variant NM_000329.3(RPE65):c.246-11A>G

dbSNP: rs905365719

Total submissions: 7

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	RCV003770300	SCV004697430	likely pathogenic	RPE65-related recessive retinopathy	2024-02-01	reviewed by expert panel	curation	NM_000329.3(RPE65):c.246-11A>G is a variant within intron 3 adjacent to exon 4. The splicing impact predictor SpliceAI gives scores of 0.48 for splice acceptor loss and 0.39 for splice acceptor gain, which are above the ClinGen LCA / eoRD VCEP recommended threshold of >=0.2 and predict a damaging impact on splicing. RT-PCR of RNA extracted from patient fibroblast-derived iPSCs detected a transcript with cryptic splice site usage introducing a frameshift and a premature termination codon, as well as a smaller amount of wild-type mRNA, consistent with a nearly complete splicing defect and most of the transcript undergoing nonsense-mediated decay (PVS1(RNA)_Strong). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3:c.615_616delCA (p.Ile206Cysfs*27) variant suspected in trans (PMID: 29033008) or the NM_000329.3(RPE65):c.208T>G (p.Phe70Val) variant confirmed in trans (PMID: 33472769, which were previously classified pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including abnormal best corrected visual acuity test (1 pt), visual field defect (1 pt), absence of rod response on ERG (0.5 pts), and improvement of FST and rod function following administration of RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (10.5 total points, PMID: 33472769, PP4_Moderate). The variant is present in gnomAD v.2.1.1 at a minor allele frequency of 0.000003988, with 1 allele / 250758 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 likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1(RNA)_Strong, PM2_Supporting, PM3, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307711	SCV002600350	likely pathogenic	Leber congenital amaurosis	2022-10-08	criteria provided, single submitter	clinical testing	Variant summary: RPE65 c.246-11A>G alters a non-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: Four predict the variant creates a cryptic 3' acceptor site, one predicts the variant abolishes a canonical 3' acceptor site, and three predict the variant weakens a canonical 3' acceptor site. At least one publication reports experimental evidence showing that this variant affects mRNA splicing, resulting in the inclusion of a pseudoexon that causes a frameshift (Tucker_2015). The variant allele was found at a frequency of 4e-06 in 250758 control chromosomes (gnomAD). c.246-11A>G has been reported in the literature as a biallelic genotype in individuals affected with Leber Congenital Amaurosis and Early Onset Retinal Degeneration (e.g. Tucker_2015, Le Meur_2018, Stingl_2022). These data indicate that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002480862	SCV002776989	likely pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement	2021-11-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002570428	SCV003523306	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-11-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the RPE65 gene. It does not directly change the encoded amino acid sequence of the RPE65 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of autosomal recessive RPE65-related conditions (PMID: 26364624, 29033008, 33472769). 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 IVS3-11. ClinVar contains an entry for this variant (Variation ID: 973955). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 26364624). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001250681	SCV004209263	likely pathogenic	Leber congenital amaurosis 2	2023-06-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814022	SCV005071999	likely pathogenic	Retinal dystrophy	2009-01-01	criteria provided, single submitter	clinical testing
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001250681	SCV001425551	pathogenic	Leber congenital amaurosis 2		no assertion criteria provided	research