Submissions for variant NM_000329.3(RPE65):c.715T>G (p.Tyr239Asp)

gnomAD frequency: 0.00002  dbSNP: rs61752896

Total submissions: 7

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	RCV003764797	SCV004697378	pathogenic	RPE65-related recessive retinopathy	2024-02-18	reviewed by expert panel	curation	NM_000329.3(RPE65):c.715T>G is a predicted missense variant substituting tyrosine by aspartic acid at position 239. The computational predictor REVEL gives a score of 0.987, 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 also gives a score of 0.34 for splice acceptor gain, which is above the ClinGen LCA / eoRD VCEP recommended threshold of >=0.2 and predicts a damaging impact on splicing. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002, with 3/129118 total alleles in the European (Non-Finnish) 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 3 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 32032261). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant confirmed in trans (1 point, PMID: 26626312), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt) and significant, documented improvement of blue full-field stimulus testing after treatment with RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (8.5 points, PMID: 21911650, PP4_Moderate). The variant exhibited between 1% (PMID: 24849605) and 5% (PMID: 19431183) enzymatic activity in retinoid isomerase assays relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting). 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, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Invitae	RCV001207227	SCV001378571	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 239 of the RPE65 protein (p.Tyr239Asp). This variant is present in population databases (rs61752896, gnomAD 0.002%). This missense change has been observed in individual(s) with retinitis pigmentosa or Leber congenital amaurosis (PMID: 20801516, 22334370, 26626312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 98889). 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: 19431183, 24849605, 26427455). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000085220	SCV001764548	pathogenic	not provided	2021-04-22	criteria provided, single submitter	clinical testing	Observed in other patients with RPE65-related disorders in published literature (Galvin et al., 2005; Jacobson et al., 2009; Pasadhika et al., 2010); Published functional studies demonstrate a damaging effect on protein function and expression (Philp et al., 2009; Redmond et al., 2010; Jin et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19959640, 22334370, 19117922, 24849605, 19920137, 26427455, 19431183, 16205573)
Baylor Genetics	RCV000678618	SCV004209219	pathogenic	Leber congenital amaurosis 2	2023-10-13	criteria provided, single submitter	clinical testing
Retina International	RCV000085220	SCV000117357	not provided	not provided		no assertion provided	not provided
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678618	SCV000804706	pathogenic	Leber congenital amaurosis 2	2016-09-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831895	SCV002092762	pathogenic	Leber congenital amaurosis	2021-06-01	no assertion criteria provided	clinical testing