Submissions for variant NM_000329.3(RPE65):c.1102T>C (p.Tyr368His)

gnomAD frequency: 0.00008  dbSNP: rs62653011

Total submissions: 16

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	RCV003764626	SCV004697406	pathogenic	RPE65-related recessive retinopathy	2024-02-20	reviewed by expert panel	curation	NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) is a missense variant that replaces the tyrosine at position 368 with histidine. It has been reported in the literature in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 12960219, PMID: 25257057). The variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.11+5G>A, c.292_311del p.Ile98Hisfs*26, or p.Arg44Ter variant confirmed in trans (3 points, PMIDs: 11786058, PMID: 34492281). All of these variants were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (4 total points, PM3_VeryStrong). The variant has also been reported to segregate with childhood-onset severe retinal dystrophy through at least 1 affected meiosis from 1 family (PP1; PMID:11786058). The variant is present in gnomAD v.2.1.1 at a Grpmax allele frequency of 0.00009488, with 19/129116 in the European (Non-Finnish) 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 0.969, 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 Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3_VeryStrong, PP1, PM2_Supporting, PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Illumina Laboratory Services, Illumina	RCV000348257	SCV000358873	pathogenic	RPE65-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	Across a selection of available literature, the RPE65 c.1102T>C (p.Tyr368His) missense variant has been identified in a total of 25 individuals with RPE65-related disorders including in 17 individuals in a homozygous state, in 8 individuals in a compound heterozygous state. Phenotypes of the affected individuals included congenital retinal dystrophy and Leber congenital amaurosis. The variant was also detected in a heterozygous state in five unaffected family members (Felius et al. 2002; Yzer et al. 2003; Sundaresan et al. 2009; Ripamonti et al. 2014; Astuti et al. 2016). The p.Tyr368His variant was found in a heterozygous state in three of 2291 controls and is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in cell lines demonstrated that the p.Tyr368His variant significantly reduced enzymatic activity compared to wild type RPE65 and had decreased protein stability (Takahashi et al. 2006; Li et al. 2014). In vivo functional studies also showed that the p.Tyr368His variant reduced enzymatic activity after subretinal injection into Rpe65 knockout mice (Takahashi et al. 2006). Based on the collective evidence, the p.Tyr368His variant is classified as pathogenic for RPE65-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001054423	SCV001218736	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 368 of the RPE65 protein (p.Tyr368His). This variant is present in population databases (rs62653011, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive RPE65-related conditions (PMID: 10937591, 11786058). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29870). 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%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 16754667). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085150	SCV001480183	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085150	SCV001770725	pathogenic	not provided	2022-04-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that Y368H decreases protein levels, stability, and alters subcellular localization of the RPE65 protein (Takahashi et al., 2006); 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: 25257057, 11786058, 18774912, 28555434, 11095629, 16150724, 19753312, 17525851, 10937591, 22334370, 15288992, 26626312, 21153841, 12960219, 16754667, 30268864, 30718709, 30820146, 29074561, 32037395, 16096063, 24849605)
3billion	RCV000022749	SCV002058938	pathogenic	Retinitis pigmentosa 20	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029870, PMID:10937591, PS1_S). A different missense change at the same codon has been reported to be associated with RPE65 related disorder (PMID:16123401, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.969, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 20 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000067, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000022750	SCV004209216	pathogenic	Leber congenital amaurosis 2	2023-10-18	criteria provided, single submitter	clinical testing
OMIM	RCV000022749	SCV000044038	pathogenic	Retinitis pigmentosa 20	2003-09-01	no assertion criteria provided	literature only
OMIM	RCV000022750	SCV000044039	pathogenic	Leber congenital amaurosis 2	2003-09-01	no assertion criteria provided	literature only
Retina International	RCV000085150	SCV000117287	not provided	not provided		no assertion provided	not provided
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000022749	SCV000804702	pathogenic	Retinitis pigmentosa 20	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787920	SCV000926939	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV000022750	SCV001425567	pathogenic	Leber congenital amaurosis 2		no assertion criteria provided	research
Natera, Inc.	RCV001275328	SCV001460402	pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000085150	SCV001978929	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085150	SCV001979529	pathogenic	not provided		no assertion criteria provided	clinical testing