ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.74C>T (p.Pro25Leu)

gnomAD frequency: 0.00002  dbSNP: rs199683808
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000504723 SCV001238858 likely pathogenic Retinal dystrophy 2018-11-11 criteria provided, single submitter clinical testing
Invitae RCV001377674 SCV001575065 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 25 of the RPE65 protein (p.Pro25Leu). This variant is present in population databases (rs199683808, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive inherited retinal dystrophy (PMID: 18599565, 28041643, 30268864, 34906470). ClinVar contains an entry for this variant (Variation ID: 437985). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 18599565, 25972377). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001724032 SCV001950353 likely pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The p.Pro25Leu variant in RPE65 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM3, PS3, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Fulgent Genetics, Fulgent Genetics RCV002496962 SCV002809907 likely pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement 2021-12-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV001250673 SCV004209223 likely pathogenic Leber congenital amaurosis 2 2023-10-06 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504723 SCV000598729 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV001250673 SCV001425543 likely pathogenic Leber congenital amaurosis 2 no assertion criteria provided research
Natera, Inc. RCV001834621 SCV002092783 likely pathogenic Leber congenital amaurosis 2021-03-08 no assertion criteria provided clinical testing

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