Submissions for variant NM_000329.3(RPE65):c.560G>A (p.Gly187Glu)

gnomAD frequency: 0.00001  dbSNP: rs752058510

Total submissions: 8

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	RCV003769292	SCV004697417	pathogenic	RPE65-related recessive retinopathy	2024-02-20	reviewed by expert panel	curation	NM_000329.3(RPE65):c.560G>A is a missense variant that causes substitution of glycine with glutamic acid at position 187. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.000009590, with 2 alleles / 34536 total alleles in the Admixed American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of retinitis pigmentosa with onset at age 2 years (1 pt), night blindness (0.5 pts), visual field reduction (1 pt), bone spicule pigmentation (0.5 pts), loss of central vision (1 pt), and undetectable electroretinogram responses from rods (0.5 pts) and cones (1 pt), which together are specific for RPE65-related recessive retinopathy (5.5 pts, PMID: 34492281, PP4). This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 31878136, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through three probands plus 4 similarly affected relatives, with the variant present in the homozygous state (PP1_Strong; PMID: 31878136). The computational predictor REVEL gives a score of 0.939, which is above the ClinGen LCA / eoRD VCEP threshold of >= 0.774 and predicts a damaging effect on RPE65 function (PP3_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: PM2_Supporting, PM3, PP1_Strong, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Mendelics	RCV000986330	SCV001135303	likely pathogenic	Leber congenital amaurosis 2	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001219364	SCV001391299	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2023-11-06	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 187 of the RPE65 protein (p.Gly187Glu). This variant is present in population databases (rs752058510, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive early onset retinal disease (PMID: 29186038, 31878136; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 801497). 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 not expected to disrupt RPE65 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001585895	SCV001819392	uncertain significance	not provided	2019-08-22	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32865313, 31878136, 29186038)
DASA	RCV002255100	SCV002526419	pathogenic	RPE65-Related Disorders	2022-06-10	criteria provided, single submitter	clinical testing	The c.560G>A;p.(Gly187Glu) missense change has been observed in affected individual(s)(PMID: 29186038; 4492281; 31878136) - PS4. The variant is present at low allele frequencies population databases (rs752058510– gnomAD 0.00007965%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Gly187Glu) was detected in trans with a Pathogenic variant (PMID: 29186038; 34492281; 31878136) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 31878136) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324538	SCV004030306	pathogenic	Leber congenital amaurosis	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324537	SCV004030307	pathogenic	Retinitis pigmentosa	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Baylor Genetics	RCV000986330	SCV004209298	likely pathogenic	Leber congenital amaurosis 2	2022-06-04	criteria provided, single submitter	clinical testing