Submissions for variant NM_000329.3(RPE65):c.419G>A (p.Gly140Glu)

gnomAD frequency: 0.00014  dbSNP: rs1191496583

Total submissions: 4

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	RCV003767007	SCV004697434	likely pathogenic	RPE65-related recessive retinopathy	2024-02-01	reviewed by expert panel	curation	NM_000329.3(RPE65):c.419G>A is a missense variant causing substitution of glycine by glutamic acid at position 140. This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 30870047). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.242G>T (p.Arg81Ile) and NM_000329.3(RPE65):c.1338G>T (p.Arg446Ser) variants confirmed in trans (2 points, PMID: 30870047), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis with Leber congenital amaurosis (0.5 pts) by exome sequencing that did not provide an alternative explanation for visual impairment (2 pts), onset at 1 month of age (1 pt), undetectable ERG responses from rods (0.5 pts) and cones (1 pt), nyctalopia (0.5 pts), reduced visual acuity (1 pt), light gazing (1 pt), RPE mottling (0.5 pts), optic nerve pallor (0.5 pt), nystagmus (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt), which together are highly specific for RPE65-related recessive retinopathy (10 total points, PMID: 30870047, PP4_Moderate). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00003893, with 5 alleles / 35438 total alleles in the Admixed American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.847, which is above the ClinGen LCA / eoRD VCEP threshold of >= 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). 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_Strong, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Invitae	RCV000542372	SCV000644185	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 140 of the RPE65 protein (p.Gly140Glu). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 467827). This missense change has been observed in individual(s) with Leber congenital amaurosis or retinitis pigmentosa (PMID: 28181551, 30870047). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.01%).
Cytogenetics and Genomics Laboratory, Medical University of South Carolina	RCV000754974	SCV000803384	likely pathogenic	Leber congenital amaurosis	2018-06-01	criteria provided, single submitter	research
Baylor Genetics	RCV003470756	SCV004209212	pathogenic	Leber congenital amaurosis 2	2023-10-23	criteria provided, single submitter	clinical testing