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

gnomAD frequency: 0.00002  dbSNP: rs199683808

Total submissions: 9

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	RCV004527379	SCV005038778	pathogenic	RPE65-related recessive retinopathy	2024-04-22	reviewed by expert panel	curation	NM_000329.3(RPE65):c.74C>T is a missense variant predicted to replace proline with leucine at position 25 in exon 2 of RPE65. This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMIDs: 18599565). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were either compound heterozygous with the c.893del p.Lys298fs variant confirmed in trans (1 pt), with the Arg515Trp variant suspected in trans (0.5 pts), or with the c.11+5G>A variant suspected in trans (0.5 pts), PMIDs: 35001204, 36672611, 30025081), which were all previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). This variant has also been reported in additional probands in the compound heterozygous state with the Ala434Glu or Tyr79His variants, but these cases were not considered to avoid circularity in the application of the PM3 code or due to insufficient phenotype data (PMIDs 29033008, 32581362, 22807296). At least one proband harboring this variant exhibits a phenotype including significant, documented improvement of dark-adapted vision after treatment with RPE65 gene therapy (8 pt), congenital night blindness (0.5 pt), nystagmus (1 pt), decreased central visual acuity (1 pt), and onset between birth and age five years (1 pt), which together are highly specific for RPE65-related recessive retinopathy (11.5 points, PMID: 36672611, PP4_Moderate). The variant exhibited 7.75% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 18599565). The computational predictor REVEL gives a score of 0.898, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.0001, with 1/30582 total alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3_Strong, PP3_Moderate, PP4_Moderate, PS3_Supporting, PM3_Supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Blueprint Genetics	RCV000504723	SCV001238858	likely pathogenic	Retinal dystrophy	2018-11-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-01-29	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