ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.902A>G (p.Asn301Ser)

gnomAD frequency: 0.00009  dbSNP: rs201075875
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Total submissions: 6
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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 RCV003769048 SCV004697389 uncertain significance RPE65-related recessive retinopathy 2024-02-19 reviewed by expert panel curation NM_000329.3(RPE65):c.902A>G is a missense variant causing substitution of asparagine with serine at position 301. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00008810, with 17/129134 in the European (Non-Finnish) 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 1 proband with a diagnosis of retinitis pigmentosa 87 with choroidal involvement, which is a dominant condition and implies harboring the variant in the heterozygous state (SCV002580301.1). However, the proband was not counted for PM3 because a second variant was not reported in trans. The computational predictor REVEL gives a score of 0.304, 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, 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 RCV001097017 SCV001253268 uncertain significance Retinitis pigmentosa 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001097018 SCV001253269 uncertain significance Leber congenital amaurosis 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001245178 SCV001418448 uncertain significance Leber congenital amaurosis 2; Retinitis pigmentosa 20 2022-10-28 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 301 of the RPE65 protein (p.Asn301Ser). This variant is present in population databases (rs201075875, gnomAD 0.01%). 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: 874234). 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.
MGZ Medical Genetics Center RCV002290601 SCV002580301 uncertain significance Retinitis pigmentosa 87 with choroidal involvement 2021-11-24 criteria provided, single submitter clinical testing
Natera, Inc. RCV001828548 SCV002092754 uncertain significance Leber congenital amaurosis 2020-02-13 no assertion criteria provided clinical testing

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