Submissions for variant NM_000329.3(RPE65):c.1597T>A (p.Ser533Thr)

gnomAD frequency: 0.00001  dbSNP: rs577335767

Total submissions: 6

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	RCV003769012	SCV004697383	uncertain significance	RPE65-related recessive retinopathy	2024-02-18	reviewed by expert panel	curation	NM_000329.3:c.1597T>A is a missense variant in RPE65 causing substitution of serine with threonine at position 533. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002596, with 3 alleles / 30608 total alleles in the South Asian 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 0.568, 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 0.00 for all change types, which is below the ClinGen LCA / eoRD VCEP recommended threshold of >=0.2 and does not strongly predict an impact on splicing. At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis, however other available phenotypes are not sufficient to evaluate specificity for RPE65-related recessive retinopathy and no second variant has been identified, so PP4 is not met (PMID: 17964524). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 25097241). However, the proband was not counted for PM3_Supporting because the NM_000329.3(RPE65):c.89T>C (p.Val30Ala) variant suspected in trans has not yet been classified for RPE65-related recessive retinopathy and because sufficient phenotype information was not available. 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).
SIB Swiss Institute of Bioinformatics	RCV001089889	SCV001245396	uncertain significance	Leber congenital amaurosis 2	2020-02-14	criteria provided, single submitter	curation	This variant is interpreted as a variant of uncertain significance for Leber congenital amaurosis 2, autosomal recessive. The following ACMG Tag(s) were applied: PM2, BP4.
Invitae	RCV001210767	SCV001382272	uncertain significance	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2022-07-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 533 of the RPE65 protein (p.Ser533Thr). This variant is present in population databases (rs577335767, gnomAD 0.01%). This missense change has been observed in individual(s) with RPE65-related retinal dystrophy (PMID: 17964524, 25097241). ClinVar contains an entry for this variant (Variation ID: 870342). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001732038	SCV001983455	uncertain significance	not specified	2021-09-28	criteria provided, single submitter	clinical testing	Variant summary: RPE65 c.1597T>A (p.Ser533Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1597T>A has been reported in the literature as a compound heterozygous genotype in at-least one individual from a cohort of non-syndromic Retinitis Pigmentosa (example, Wang_2014) and as a non-informative genotype (second allele not specified) in at-least one individual affected with Leber Congenital Amaurosis (example, Stone_2007). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002489725	SCV002796325	uncertain significance	Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement	2022-01-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001828545	SCV002092729	uncertain significance	Leber congenital amaurosis	2020-02-20	no assertion criteria provided	clinical testing