Submissions for variant NM_000329.3(RPE65):c.118G>A (p.Gly40Ser)

gnomAD frequency: 0.00003  dbSNP: rs61751281

Total submissions: 10

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	RCV004527312	SCV005038791	pathogenic	RPE65-related recessive retinopathy	2024-04-22	reviewed by expert panel	curation	NM_000329.3(RPE65):c.118G>A is a missense variant predicted to replace glycine with serine at position 40. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00006, with 2 alleles/24966 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). The computational predictor REVEL gives a score of 0.984, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited <2 % enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 16150724 ). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 25257057, PMID: 33608557). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variant confirmed in trans (1 pt, PMID: 9501220, PMID: 11462243), the c.11+5G>A variant suspected in trans (0.5 pts, PMID: 18441371), or the p.Arg91Gln variant suspected in trans (0.5 pts, PMID: 19117922), all of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (total 3 pts, PM3_Strong). 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: 9501220, PP1). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), absent or severely reduced rod ERG (0.5 pts), decreased central visual acuity (1 pt), and significant improvement of visual function by FST after gene-specific gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (total 10 pts, PMID: 21911650, PP4_Moderate). 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: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
GeneDx	RCV000085155	SCV000329701	pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on protein expression and isomerization activity (Li S et al., 2014; Redmond TM et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16150724, 15691574, 19959640, 19117922, 29332120, 29785639, 9501220, 25257057, 24849605)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047503	SCV001211466	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 40 of the RPE65 protein (p.Gly40Ser). This variant is present in population databases (rs61751281, gnomAD 0.01%). This missense change has been observed in individuals with RPE65-related disease (PMID: 9501220, 25257057, 29332120, 29785639). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98830). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 16150724, 19431183). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074416	SCV001239998	pathogenic	Retinal dystrophy	2019-08-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498450	SCV002811531	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement	2021-09-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001250675	SCV004209218	pathogenic	Leber congenital amaurosis 2	2024-03-30	criteria provided, single submitter	clinical testing
Retina International	RCV000085155	SCV000117292	not provided	not provided		no assertion provided	not provided
Department of Ophthalmology and Visual Sciences Kyoto University	RCV000132582	SCV000172525	pathogenic	Retinitis pigmentosa		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001250675	SCV001425545	pathogenic	Leber congenital amaurosis 2		no assertion criteria provided	research
Natera, Inc.	RCV001275340	SCV001460414	pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing