rs62653011

Positions:

chr1-68438213-A-G

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP1PM3PM2_SupportingPP3_Moderate

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) is a missense variant that replaces the tyrosine at position 368 with histidine. It has been reported in the literature in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID:12960219, PMID:25257057). The variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.11+5G>A, c.292_311del p.Ile98Hisfs*26, or p.Arg44Ter variant confirmed in trans (3 points, PMIDs: 11786058, PMID:34492281). All of these variants were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (4 total points, PM3_VeryStrong). The variant has also been reported to segregate with childhood-onset severe retinal dystrophy through at least 1 affected meiosis from 1 family (PP1; PMID:11786058). The variant is present in gnomAD v.2.1.1 at a Grpmax allele frequency of 0.00009488, with 19/129116 in the European (Non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.969, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). 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_VeryStrong, PP1, PM2_Supporting, PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226484/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

RPE65
NM_000329.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:16O: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]

RPE65 links:

LOC124904198 (HGNC:):

LOC124904198 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 6 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPE65	NM_000329.3 linkuse as main transcript	c.1102T>C	p.Tyr368His	missense_variant	10/14	ENST00000262340.6	NP_000320.1	Q16518

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6 linkuse as main transcript	c.1102T>C	p.Tyr368His	missense_variant	10/14	1	NM_000329.3	ENSP00000262340.5		Q16518

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251300

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000148

AC:

217

AN:

1461684

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

109

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000191

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000122

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2022	Published functional studies demonstrate that Y368H decreases protein levels, stability, and alters subcellular localization of the RPE65 protein (Takahashi et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25257057, 11786058, 18774912, 28555434, 11095629, 16150724, 19753312, 17525851, 10937591, 22334370, 15288992, 26626312, 21153841, 12960219, 16754667, 30268864, 30718709, 30820146, 29074561, 32037395, 16096063, 24849605) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -

Leber congenital amaurosis 2

Pathogenic:3

Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -

Retinitis pigmentosa 20

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2003	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029870, PMID:10937591, PS1_S). A different missense change at the same codon has been reported to be associated with RPE65 related disorder (PMID:16123401, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.969, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 20 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000067, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

RPE65-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Across a selection of available literature, the RPE65 c.1102T>C (p.Tyr368His) missense variant has been identified in a total of 25 individuals with RPE65-related disorders including in 17 individuals in a homozygous state, in 8 individuals in a compound heterozygous state. Phenotypes of the affected individuals included congenital retinal dystrophy and Leber congenital amaurosis. The variant was also detected in a heterozygous state in five unaffected family members (Felius et al. 2002; Yzer et al. 2003; Sundaresan et al. 2009; Ripamonti et al. 2014; Astuti et al. 2016). The p.Tyr368His variant was found in a heterozygous state in three of 2291 controls and is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in cell lines demonstrated that the p.Tyr368His variant significantly reduced enzymatic activity compared to wild type RPE65 and had decreased protein stability (Takahashi et al. 2006; Li et al. 2014). In vivo functional studies also showed that the p.Tyr368His variant reduced enzymatic activity after subretinal injection into Rpe65 knockout mice (Takahashi et al. 2006). Based on the collective evidence, the p.Tyr368His variant is classified as pathogenic for RPE65-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

RPE65-related recessive retinopathy

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen

Feb 20, 2024

NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) is a missense variant that replaces the tyrosine at position 368 with histidine. It has been reported in the literature in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 12960219, PMID: 25257057). The variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.11+5G>A, c.292_311del p.Ile98Hisfs*26, or p.Arg44Ter variant confirmed in trans (3 points, PMIDs: 11786058, PMID: 34492281). All of these variants were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (4 total points, PM3_VeryStrong). The variant has also been reported to segregate with childhood-onset severe retinal dystrophy through at least 1 affected meiosis from 1 family (PP1; PMID:11786058). The variant is present in gnomAD v.2.1.1 at a Grpmax allele frequency of 0.00009488, with 19/129116 in the European (Non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.969, which is above the ClinGen LCA/eoRD VCEP threshold of >= 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). 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_VeryStrong, PP1, PM2_Supporting, PP3_Moderate. (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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 368 of the RPE65 protein (p.Tyr368His). This variant is present in population databases (rs62653011, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive RPE65-related conditions (PMID: 10937591, 11786058). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29870). 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: 16754667). For these reasons, this variant has been classified as Pathogenic. -

Leber congenital amaurosis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2019

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.98

MPC

0.15

ClinPred

0.63

GERP RS

5.7

Varity_R

0.93

gMVP

0.90

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over