ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.1580A>G (p.His527Arg)

dbSNP: rs1194458561
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Total submissions: 3
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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 RCV004527438 SCV005038764 likely pathogenic RPE65-related recessive retinopathy 2024-04-22 reviewed by expert panel curation NM_000329.3(RPE65):c.1580A>G is a missense variant predicted to replace histidine with arginine at position 527, which is located within the active site, a well-characterized functional domain required for enzymatic activity (PM1, PMID: 34492281). This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.000008877, with 1 allele / 112652 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). At least one proband harboring this variant exhibits a phenotype of retinitis pigmentosa with early childhood onset including progressive vision loss (1 pt), early onset nyctalopia (0.5 pts), severely depressed electroretinography responses from rods (0.5 pts) and cones (1 pt), tritanomaly, white retinal flecks (2 pts), retinal pigment epithelium mottling (0.5 pts), attenuated retinal vessels (0.5 pts), complete loss of peripheral fundus autofluorescence (2 pts), and outer nuclear layer thickness at the low end of the normal range, which together are highly specific for RPE65-related recessive retinopathy (total 8 pts, PMID: 17525851, PP4_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.499G>T (p.Asp167Tyr) variant confirmed in trans, however, PM3 was not considered to avoid circularity (PMID: 35904185). A second proband with early-onset severe retinal dystrophy harbored the variant in the heterozygous state but was not counted for PM3 because the second variant NM_000329.3(RPE65):c.651del (p.Asp218IlefsTer3) was apparently in cis (PMID: 17525851). The computational predictor REVEL gives a score of 0.991, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 24849605). 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: PS3_Supporting, PM1, PM2_Supporting, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Invitae RCV001982688 SCV002225446 uncertain significance Leber congenital amaurosis 2; Retinitis pigmentosa 20 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 527 of the RPE65 protein (p.His527Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of RPE65-related conditions (PMID: 17525851). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RPE65 function (PMID: 24849605). 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.
Baylor Genetics RCV004571683 SCV005055442 likely pathogenic Leber congenital amaurosis 2 2024-01-11 criteria provided, single submitter clinical testing

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