Submissions for variant NM_000329.3(RPE65):c.242G>T (p.Arg81Ile)

gnomAD frequency: 0.00009  dbSNP: rs1429137932

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	RCV004527393	SCV005038766	pathogenic	RPE65-related recessive retinopathy	2024-04-22	reviewed by expert panel	curation	NM_000329.3(RPE65):c.242G>T is a missense variant causing substitution of arginine by isoleucine at position 81. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.0001576, with 24 alleles / 59020 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 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 30870047). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.2(RPE65):c.292_311del (p.Ile98Hisfs) variant confirmed in trans (1 pt, PMID: 30870047), 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 a diagnosis of Leber congenital amaurosis (0.5 pts), onset at 1 month of age (1 pt), undetectable ERG responses from rods (0.5 pts) and cones (1 pt), nyctalopia (0.5 pts), reduced visual acuity (1 pt), light gazing (1 pt), RPE mottling (0.5 pts), optic nerve pallor (0.5 pt), nystagmus (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total points, PMID: 30870047, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state (PMID: 30870047, PP1). The computational predictor REVEL gives a score of 0.849, 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).
Cytogenetics and Genomics Laboratory, Medical University of South Carolina	RCV000754977	SCV000803387	likely pathogenic	Leber congenital amaurosis	2018-06-01	criteria provided, single submitter	research
Invitae	RCV001053470	SCV001217734	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 81 of the RPE65 protein (p.Arg81Ile). This variant is present in population databases (no rsID available, gnomAD 0.03%). This missense change has been observed in individuals with Leber congenital amaurosis (PMID: 30870047). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 559523). 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.
Illumina Laboratory Services, Illumina	RCV001098872	SCV001255269	uncertain significance	Leber congenital amaurosis 2	2018-02-16	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001098873	SCV001255270	uncertain significance	Retinitis pigmentosa	2018-02-16	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001756143	SCV001986880	uncertain significance	not provided	2019-12-19	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30870047)
3billion	RCV001098872	SCV002572586	likely pathogenic	Leber congenital amaurosis 2	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.68). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000559523). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.