Submissions for variant NM_000329.3(RPE65):c.565G>A (p.Val189Ile)

gnomAD frequency: 0.00005  dbSNP: rs752990312

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	RCV003769067	SCV004697387	uncertain significance	RPE65-related recessive retinopathy	2024-02-19	reviewed by expert panel	curation	NM_000329.3(RPE65):c.565G>A is a missense variant causing substitution of valine with isoleucine at position 189. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00009487, with 7 alleles / 35374 total alleles in the Admixed American 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 a diagnosis of retinitis pigmentosa who harbored the variant in the heterozygous state (PMID: 18722466). However, PM3 was not met because no second variant was described. The computational predictor REVEL gives a score of 0.464, which is below the ClinGen LCA / eoRD VCEP threshold of >=0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.02 for acceptor loss and donor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of >=0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a variant uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Illumina Laboratory Services, Illumina	RCV001100592	SCV001257120	uncertain significance	Leber congenital amaurosis 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001100593	SCV001257121	uncertain significance	Retinitis pigmentosa	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001585980	SCV001821531	uncertain significance	Retinitis pigmentosa 20	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001100592	SCV001821642	uncertain significance	Leber congenital amaurosis 2	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002554965	SCV003278901	uncertain significance	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 189 of the RPE65 protein (p.Val189Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with retinal disease (PMID: 18722466; Invitae). ClinVar contains an entry for this variant (Variation ID: 876133). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Dept Of Ophthalmology, Nagoya University	RCV003890245	SCV004706374	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research