Submissions for variant NM_000329.3(RPE65):c.499G>T (p.Asp167Tyr)

gnomAD frequency: 0.00001  dbSNP: rs61752883

Total submissions: 11

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	RCV004527316	SCV005038772	pathogenic	RPE65-related recessive retinopathy	2024-07-23	reviewed by expert panel	curation	NM_000329.3(RPE65):c.499G>T (p.Asp167Tyr) is a missense variant predicted to replace aspartic acid with tyrosine at position 167. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.000007020 with 3 alleles / 113490 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 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 36547097). This variant has also been reported in at least 5 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.16G>T (p.Glu6Ter), NM_000329.3(RPE65):c.292_311del (p.Ile98HisfsTer26), NM_000329.3(RPE65):c.938A>G (p.His313Arg), or NM_000329.3(RPE65):c.778_785del (p.Asn260GlnfsTer18) variants suspected in trans (2 pts, PMID: 11095629, PMID: 35129589, PMID: 25257057), as well as the NM_000329.3(RPE65):c.11+5G>A variant confirmed in trans (1 pt, PMID: 35904185, PMID: 28224992), all of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (3.5 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts, PMID: 25257057), undetectable ERG response from rods (0.5 pts) and reduced ERG responses from cones (1 pt, PMID: 18441371) and significant, documented improvement of retinal sensitivity by dark-adapted perimetry and microperimetry after treatment with RPE65 gene therapy (8 pts, PMID: 25938638), which together are highly specific for RPE65-related recessive retinopathy (total 10 pts, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through a proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 28224992, PP1). The computational predictor REVEL gives a score of 0.93, 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: PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
GeneDx	RCV000085203	SCV000491115	likely pathogenic	not provided	2022-07-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 15288992, 18441371, 18774912, 17964524, 18055820, 25257057, 17724218, 11095629, 32032261)
Illumina Laboratory Services, Illumina	RCV000778252	SCV000914424	likely pathogenic	RPE65-related disorder	2018-12-11	criteria provided, single submitter	clinical testing	The RPE65 c.499G>T (p.Asp167Tyr) variant is a missense variant that has been reported in a compound heterozygous state in three individuals with either Leber congenital amaurosis or retinal dystrophy (Thompson et al. 2000; Simonelli et al. 2007; Bainbridge et al. 2008; Ripamonti et al. 2014). The p.Asp167Tyr variant was also identified in a heterozygous state in one additional case in whom a second variant was not identified (Henderson et al. 2007). The p.Asp167Tyr variant was absent from 50 control individuals but was reported at a frequency of 0.000026 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies of this variant have not been conducted, but it affects a conserved residue and in silico tools predict it to have a damaging effect. Based on the collective evidence, the p.Asp167Tyr variant is classified as likely pathogenic for RPE65-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245153	SCV001418423	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 167 of the RPE65 protein (p.Asp167Tyr). This variant is present in population databases (rs61752883, gnomAD 0.003%). This missense change has been observed in individual(s) with retinal dystrophy (PMID: 11095629, 17724218, 18441371, 25257057, 28224992). 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: 98873). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RPE65 protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001831894	SCV002547975	pathogenic	Leber congenital amaurosis	2022-05-26	criteria provided, single submitter	clinical testing	Variant summary: RPE65 c.499G>T (p.Asp167Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250964 control chromosomes. c.499G>T has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis, Inherited Retinal Degeneration, or other Retinitis pigmentosa. These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic n=1, likely pathogenic n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001250708	SCV004209308	pathogenic	Leber congenital amaurosis 2	2024-02-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031581	SCV005663977	likely pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement	2024-02-29	criteria provided, single submitter	clinical testing
Retina International	RCV000085203	SCV000117340	not provided	not provided		no assertion provided	not provided
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678617	SCV000804705	uncertain significance	Retinitis pigmentosa 20	2016-09-01	no assertion criteria provided	clinical testing
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001250708	SCV001425586	likely pathogenic	Leber congenital amaurosis 2		no assertion criteria provided	research
Natera, Inc.	RCV001831894	SCV002092769	likely pathogenic	Leber congenital amaurosis	2021-05-04	no assertion criteria provided	clinical testing