Submissions for variant NM_000329.3(RPE65):c.1451G>A (p.Gly484Asp)

dbSNP: rs62653015

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	RCV003764788	SCV004697408	likely pathogenic	RPE65-related recessive retinopathy	2024-01-31	reviewed by expert panel	curation	NM_000329.3(RPE65):c.1451G>A is a predicted missense variant substituting glycine by aspartic acid at position 484. The computational predictor REVEL gives a score of 0.984, which is above the ClinGen LCA / eoRD VCEP threshold of >=0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). Additionally, the splicing impact predictor SpliceAI gives a score of 0.23, which is above the ClinGen LCA / eoRD VCEP recommended threshold of >= 0.2 and predicts a damaging impact on splicing. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00005447, with 1/18360 total alleles in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002. This variant has been reported in least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 30025081, PM3). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pts), absent or severely decreased rod electroretinogram response (0.5 pts), abnormal cone ERG responses (1 pt), white dots on color photography in the context of severe retinal dysfunction (2 pts), poor pupillary light response (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), decreased central visual acuity (1 pt), RPE mottling (0.5 pts), macular atrophy (0.5 pts), and symptomatic onset between birth and age five years (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total points, PMID: 20811047, PP4_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
GeneDx	RCV000085175	SCV000565496	likely pathogenic	not provided	2016-08-16	criteria provided, single submitter	clinical testing	The G484D variant has been reported previously in association with autosomal recessive retinitis pigmentosa (Stone et al., 2003) and in another individual with Severe Early Childhood Onset Retinal Dystrophy (SECORD) presenting with a remarkable preservation of vision with adequate lighting and white retinal dots that were seen to fade with time and were replaced by RPE changes (Weleber et al., 2011). The G484D variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G484D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. One other variant in a nearby residue (D477G) has been reported in the Human Gene Mutation Database in association with and RPE65-related disorder (Stenson et al., 2014). Therefore, based on the currently available information, G484D is a likely pathogenic variant.
Revvity Omics, Revvity	RCV000085175	SCV002019069	likely pathogenic	not provided	2020-11-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854497	SCV002266185	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 484 of the RPE65 protein (p.Gly484Asp). This variant is present in population databases (rs62653015, gnomAD 0.006%). This missense change has been observed in individual(s) with RPE65-related conditions (PMID: 20811047, 29332120, 30653986; internal data). 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: 98848). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly484 amino acid residue in RPE65. Other variant(s) that disrupt this residue have been observed in individuals with RPE65-related conditions (PMID: 33308271), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001826773	SCV003800728	likely pathogenic	Leber congenital amaurosis	2023-01-31	criteria provided, single submitter	clinical testing	Variant summary: RPE65 c.1451G>A (p.Gly484Asp) 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 248526 control chromosomes (gnomAD). c.1451G>A has been reported in the literature in individuals affected with RPE65-related conditions (examples: Weleber_2011, Biswas_2017, Kumaran_2018, Chung_2019, Patel_2019, Lopez-Rodriguez_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001826773	SCV004012155	pathogenic	Leber congenital amaurosis	2023-07-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001250703	SCV004209260	likely pathogenic	Leber congenital amaurosis 2	2024-03-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025144	SCV005660807	likely pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement	2024-06-18	criteria provided, single submitter	clinical testing
Retina International	RCV000085175	SCV000117312	not provided	not provided		no assertion provided	not provided
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001250703	SCV001425578	likely pathogenic	Leber congenital amaurosis 2		no assertion criteria provided	research
Natera, Inc.	RCV001826773	SCV002092736	likely pathogenic	Leber congenital amaurosis	2020-09-24	no assertion criteria provided	clinical testing