Submissions for variant NM_000329.3(RPE65):c.1101A>G (p.Arg367=)

dbSNP: rs1553152989

Total submissions: 6

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	RCV004527377	SCV005038789	pathogenic	RPE65-related recessive retinopathy	2024-04-22	reviewed by expert panel	curation	NM_000329.3(RPE65):c.1101A>G (p.Arg367=) is a synonymous variant located in the third nucleotide of exon 10. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The splicing impact predictor SpliceAI gives a score of 0.99 for donor gain, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. This prediction has been confirmed by a minigene assay showing complete disruption of splicing and production of an alternative transcript with an out-of-frame truncation of 28 base pairs, which is supportive of a damaging effect on protein function (PMID: 28714225). These in silico and experimental findings have not been used to meet the PP3 and PS3_Supporting codes, but rather combined to meet the PVS1(RNA) code. At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts), previous 100+ retinal dystrophy gene panel testing that did not provide an alternative explanation for visual impairment (2 pts), decreased central visual acuity (1 pt), onset between birth and 5 years old (1 pt), pigmentary retinopathy with attenuated vessels (0.5 pts), RPE mottling (0.5 pts) and macular atrophy (0.5 pts), which together are specific for RPE65-related recessive retinopathy (6 pts, PMID: 28714225, PMID: 32865313, PP4). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) or NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) variants suspected in trans (1 point, PMID: 36909829, 28714225), which were previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (PM3). 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, PM3, PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Invitae	RCV001865522	SCV002168882	uncertain significance	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2022-01-11	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28714225). ClinVar contains an entry for this variant (Variation ID: 427868). This variant has been observed in individual(s) with Leber congenital amaurosis (PMID: 28714225). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 367 of the RPE65 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RPE65 protein.
Mendelics	RCV002248718	SCV002518986	pathogenic	Leber congenital amaurosis 2	2022-05-04	criteria provided, single submitter	clinical testing
3billion	RCV002248718	SCV002521227	likely pathogenic	Leber congenital amaurosis 2	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.99). The variant is in trans with the other variant (3billion dataset). The variant has been reported to be associated with RPE65 related disorder (ClinVar ID: VCV000427868). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV000515747	SCV004030304	likely pathogenic	Leber congenital amaurosis	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Rui Chen Lab, Baylor College of Medicine	RCV000515747	SCV000579425	pathogenic	Leber congenital amaurosis	2017-05-09	no assertion criteria provided	research