Submissions for variant NM_000329.3(RPE65):c.124C>T (p.Leu42Phe)

gnomAD frequency: 0.00001  dbSNP: rs750724065

Total submissions: 5

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	RCV004801934	SCV005423713	likely pathogenic	RPE65-related recessive retinopathy	2024-12-12	reviewed by expert panel	curation	NM_000329.3(RPE65):c.124C>T is a missense variant that replaces leucine with phenylalanine at position 42. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.00003588, with 7 alleles / 91068 total alleles in the South Asian population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). 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.130C>T (p.Arg44Ter) variant (PMID: 30996589) or the NM_000329.3(RPE65):c.495+1dup variant (VCEP member-provided data) suspected in trans, both of which were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset in the first few months of life (1 pt), genotyping by targeted exome sequencing focused on 194 IRD genes without identifying an alternative basis for disease (2 points), poor vision limited to hand movement (1 pt), nystagmus (1 pt), maculopathy (0.5 pts), peripheral hyperpigmentation, and retinal vascular attenuation (0.5 pts), which together are specific for RPE65-related recessive retinopathy (total 6.5 points, PMID: 30996589, PP4). The computational predictor REVEL gives a score of 0.879, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.01 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. A molecular dynamics and simulation-based model of the variant predicts that the variant would destabilize the structure of RPE65 (PMID: 32072079). However, this is not currently an approved form of functional evidence, so the PS3_Supporting code is not met. 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: PM2_supporting, PM3, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243775	SCV001416957	uncertain significance	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2022-08-06	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 42 of the RPE65 protein (p.Leu42Phe). This variant is present in population databases (rs750724065, gnomAD 0.01%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 30996589). ClinVar contains an entry for this variant (Variation ID: 968598). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPE65 protein function. 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.
GeneDx	RCV001773551	SCV001994269	uncertain significance	not provided	2019-07-05	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30996589, 32072079)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV004556080	SCV005045212	likely pathogenic	Retinitis pigmentosa 20	2024-05-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001829042	SCV002092778	uncertain significance	Leber congenital amaurosis	2020-03-10	no assertion criteria provided	clinical testing