Submissions for variant NM_000329.3(RPE65):c.845A>G (p.Asn282Ser)

gnomAD frequency: 0.00004  dbSNP: rs144612129

Total submissions: 5

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	RCV004595856	SCV005088575	uncertain significance	RPE65-related recessive retinopathy	2024-07-23	reviewed by expert panel	curation	NM_000329.3(RPE65):c.845A>G (p.Asn282Ser) is a missense variant resulting in substitution of asparagine by serine at codon 282. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00009682, with 11 alleles / 113616 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). The computational predictor REVEL gives a score of 0.435, which is above 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 0.00, 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 of 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	RCV000305340	SCV000358878	uncertain significance	Leber congenital amaurosis 2	2018-01-12	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	RCV000360661	SCV000358879	uncertain significance	Retinitis pigmentosa	2018-01-12	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.
Fulgent Genetics, Fulgent Genetics	RCV002502181	SCV002814339	uncertain significance	Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement	2021-07-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002520509	SCV003243028	uncertain significance	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 282 of the RPE65 protein (p.Asn282Ser). This variant is present in population databases (rs144612129, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with RPE65-related conditions. ClinVar contains an entry for this variant (Variation ID: 298022). 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.