Submissions for variant NM_000329.3(RPE65):c.1360del (p.Thr454fs)

dbSNP: rs2100807036

Total submissions: 2

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	RCV004527440	SCV005038759	pathogenic	RPE65-related recessive retinopathy	2024-04-22	reviewed by expert panel	curation	NM_000329.3(RPE65):c.1360del (p.Thr454LeufsTer?) is a frameshift variant that introduces a premature stop codon into exon 13 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). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including severely decreased ERG responses (0.5 pts), optic disc pallor (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), symptomatic onset between birth and age five years (1 pt), decreased peripheral vision (1 pt), abnormal color vision (1 pt), decreased central visual acuity (1 pt), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID: 28130426, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 28130426, PP1). 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, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002037689	SCV002234726	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2022-03-10	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RPE65 protein in which other variant(s) (p.Phe530Leu) have been determined to be pathogenic (PMID: 25383945, 26047050, 33952291). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with rod-cone dystrophy (PMID: 28130426). 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. This sequence change creates a premature translational stop signal (p.Thr454Leufs*32) in the RPE65 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acid(s) of the RPE65 protein.