rs61752909

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4_ModeratePM2_SupportingPM3_StrongPP1_StrongPP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) missense variant replaces the leucine at position 341 with serine and has been reported in several patients. At least one patient (analyzed on a 100+ retinal dystrophy gene panel testing (2 pt) in PMID:23847139) who displayed a non-detectable ERG (2 pt), visual acuity 20/400 OD and OS (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (1 pt), and no pigment in peripheral retina, which is highly specific for RPE65 retinopathy (PP4_Moderate). One patient was compound heterozygous for this variant and a pathogenic pathogenic variant (c.1205_1206insCCTG classified Pathogenic by the LCA/eoRD VCEP) confirmed in trans by parental testing (PMID:9501220) and two probands were homozygous for the variant (PMID:9501220, PMID:15837919) (PM3_strong). The variant has been reported to segregate with RPE65 retinopathy (confirmed by absent or severely decreased rod electroretinogram response) in the proband plus 3 affected family members, all with the compound heterozygous genotype of Leu341Ser and c.1205_1206insCCTG variants. (PP1_strong; PMID:9501220). The computational predictor REVEL gives a score of 0.988 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is absent from gnomAD v2.1.1 and has a Grpmax Filtering AF of 0.00005290 in gnomAD v.3.1.2 (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: PP1_strong, PM3_strong, PP3_Moderate, PP4_Moderate, PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226472/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

RPE65
NM_000329.3 missense

Scores

11
4
4

Clinical Significance

Pathogenic reviewed by expert panel P:14O:1

Conservation

PhyloP100: 8.84
Variant links:
Genes affected
RPE65 (HGNC:10294): (retinoid isomerohydrolase RPE65) The protein encoded by this gene is a component of the vitamin A visual cycle of the retina which supplies the 11-cis retinal chromophore of the photoreceptors opsin visual pigments. It is a member of the carotenoid cleavage oxygenase superfamily. All members of this superfamily are non-heme iron oxygenases with a seven-bladed propeller fold and oxidatively cleave carotenoid carbon:carbon double bonds. However, the protein encoded by this gene has acquired a divergent function that involves the concerted O-alkyl ester cleavage of its all-trans retinyl ester substrate and all-trans to 11-cis double bond isomerization of the retinyl moiety. As such, it performs the essential enzymatic isomerization step in the synthesis of 11-cis retinal. Mutations in this gene are associated with early-onset severe blinding disorders such as Leber congenital. [provided by RefSeq, Oct 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RPE65NM_000329.3 linkuse as main transcriptc.1022T>C p.Leu341Ser missense_variant 10/14 ENST00000262340.6 NP_000320.1 Q16518

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RPE65ENST00000262340.6 linkuse as main transcriptc.1022T>C p.Leu341Ser missense_variant 10/141 NM_000329.3 ENSP00000262340.5 Q16518

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461324
Hom.:
0
Cov.:
32
AF XY:
0.00000688
AC XY:
5
AN XY:
726994
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152164
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000279
Hom.:
0
Bravo
AF:
0.0000416

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Leber congenital amaurosis 2 Pathogenic:4
Pathogenic, no assertion criteria providedresearchLaboratory of Genetics in Ophthalmology, Institut Imagine-- -
Pathogenic, criteria provided, single submitterclinical testing3billionMay 22, 2022The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013118). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 20079931) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:9501220). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 30, 2023- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Leber congenital amaurosis Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 14, 2024Variant summary: RPE65 c.1022T>C (p.Leu341Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250484 control chromosomes. c.1022T>C has been reported in the literature in multiple individuals affected with Retinitis pigmentosa (Morimura_1998). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 9501220). ClinVar contains an entry for this variant (Variation ID: 13118). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 18, 2020- -
Likely pathogenic, criteria provided, single submitterresearchOphthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology BaselJul 24, 2023Clinical significance based on ACMG v2.0 -
Retinitis pigmentosa 20 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenJun 05, 2023- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 17, 1998- -
not provided Pathogenic:1Other:1
not provided, no classification providedliterature onlyRetina International-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 19, 2021Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32865313, 32036094, 19854499, 21862650, 19753312, 30268864, 9501220, 29186038, 20079931, 20683928, 20811047, 27375040, 19117922, 18539930, 21153841, 10800710, 17964524) -
RPE65-related recessive retinopathy Pathogenic:1
Pathogenic, reviewed by expert panelcurationClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGenFeb 20, 2024The NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) missense variant replaces the leucine at position 341 with serine and has been reported in several patients. At least one patient (analyzed on a 100+ retinal dystrophy gene panel testing (2 pt) in PMID: 23847139) who displayed a non-detectable ERG (2 pt), visual acuity 20/400 OD and OS (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (1 pt), and no pigment in peripheral retina, which is highly specific for RPE65 retinopathy (PP4_Moderate). One patient was compound heterozygous for this variant and a pathogenic pathogenic variant (c.1205_1206insCCTG classified Pathogenic by the LCA/eoRD VCEP) confirmed in trans by parental testing (PMID: 9501220) and two probands were homozygous for the variant (PMID: 9501220, PMID: 15837919) (PM3_strong). The variant has been reported to segregate with RPE65 retinopathy (confirmed by absent or severely decreased rod electroretinogram response) in the proband plus 3 affected family members, all with the compound heterozygous genotype of Leu341Ser and c.1205_1206insCCTG variants. (PP1_strong; PMID: 9501220). The computational predictor REVEL gives a score of 0.988 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is absent from gnomAD v2.1.1 and has a Grpmax Filtering AF of 0.00005290 in gnomAD v.3.1.2 (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: PP1_strong, PM3_strong, PP3_Moderate, PP4_Moderate, PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -
Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 341 of the RPE65 protein (p.Leu341Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Leber congenital amaurosis or retinitis pigmentosa (PMID: 9501220, 18539930, 19854499, 20079931, 20683928). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13118). 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 expected to disrupt RPE65 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20;C5231465:Retinitis pigmentosa 87 with choroidal involvement Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 12, 2021- -
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
D
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.77
T
M_CAP
Pathogenic
0.47
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Benign
2.0
M
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.4
N
REVEL
Pathogenic
0.88
Sift
Uncertain
0.017
D
Sift4G
Uncertain
0.0070
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.83
Gain of catalytic residue at L341 (P = 0.0097);
MVP
0.99
MPC
0.41
ClinPred
0.98
D
GERP RS
5.7
Varity_R
0.68
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61752909; hg19: chr1-68903976; API