chr1-68444858-G-A

Position:

chr1-68444858-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PP3_ModeratePP1_ModeratePS3_SupportingPP4_ModeratePM3_StrongPM2_SupportingPM5

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) is a missense variant predicted to replace arginine with tryptophan at position 91. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.0001329, with 16 alleles / 74990 total alleles in the African / African-American 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 4 apparently unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 35129589, 18722466). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.11+5G>A or NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) variants suspected in trans (1 point, PMIDs: 35129589, 33952291), both of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant was genotyped by next-generation sequencing analysis of 586 candidate genes which did not provide an alternative explanation for visual impairment (2 pts) and exhibits a phenotype including congenital onset (1 pt), abnormal best corrected visual acuity test (1 pt), mild myopia, extinguished scotopic (0.5 pts) and photopic (1 pt) ERG responses, bone spicule pigmentation of the fundus (0.5 pts), white or yellow dots in fundus (2 pts), and nystagmus (1 pt), which together are highly specific for RPE65-related recessive retinopathy (9 total points, PMID:31925606, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PMID:31925606, PP1_Moderate). The computational predictor REVEL gives a score of 0.852, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.22, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥ 0.2 and predicts a damaging impact on splicing. Another missense variant in the same codon, NM_000329.3(RPE65):c.272G>A (p.Arg91Gln), has been classified as pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5). Splicing predictions using SpliceAI are equivalent for both of these variants. The variant exhibited 0% 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 (PMID:16754667, PS3_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: PM2_Supporting, PM3_strong, PP4_moderate, PP1_moderate, PP3_moderate, PM5, and PS3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226531/MONDO:0100368/120

Frequency

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

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

RPE65
NM_000329.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:16O:1

Conservation

PhyloP100: 3.08

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 14 ACMG points.

PS3

PM2

PM3

PM5

PP1

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPE65	NM_000329.3 linkuse as main transcript	c.271C>T	p.Arg91Trp	missense_variant	4/14	ENST00000262340.6
LOC124904198	XR_007066164.1 linkuse as main transcript	n.72-3674G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPE65	ENST00000262340.6 linkuse as main transcript	c.271C>T	p.Arg91Trp	missense_variant	4/14	1	NM_000329.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251212

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000746

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2022	Published functional studies demonstrate a damaging effect with decreased enzyme activity, decreased protein expression, and accelerated degradation compared to wild type (Takahashi et al., 2006; Li et al., 2015); This variant is associated with the following publications: (PMID: 16205573, 16518657, 19117922, 17197551, 18936139, 9501220, 18682808, 18539930, 18722466, 11095629, 16505056, 18809924, 30268864, 19431183, 25257057, 25752820, 19854499, 17525851, 24997176, 21911650, 18774912, 10937591, 10766140, 17964524, 17933883, 21304899, 27874104, 26427430, 31054281, 31925606, 22334370, 16754667, 31273949) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	RPE65: PM3:Very Strong, PM2, PM5, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 13, 2023	- -
not provided, no classification provided	literature only	Retina International	-	- -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 16, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 91 of the RPE65 protein (p.Arg91Trp). This variant is present in population databases (rs61752871, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive RPE65-related conditions (PMID: 9501220, 10766140, 10937591, 11095629, 18682808, 26626312; Invitae). 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: 13115). 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 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 16754667, 25752820). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Leber congenital amaurosis 2

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

Retinitis pigmentosa 20

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 17, 1998	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The RPE65 c.271C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PP1-S, PM2. Based on this evidence we have classified this variant as Pathogenic. -

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

Jul 23, 2024

NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) is a missense variant predicted to replace arginine with tryptophan at position 91. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.0001329, with 16 alleles / 74990 total alleles in the African / African-American 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 4 apparently unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 35129589, 18722466). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.11+5G>A or NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) variants suspected in trans (1 point, PMIDs: 35129589, 33952291), both of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant was genotyped by next-generation sequencing analysis of 586 candidate genes which did not provide an alternative explanation for visual impairment (2 pts) and exhibits a phenotype including congenital onset (1 pt), abnormal best corrected visual acuity test (1 pt), mild myopia, extinguished scotopic (0.5 pts) and photopic (1 pt) ERG responses, bone spicule pigmentation of the fundus (0.5 pts), white or yellow dots in fundus (2 pts), and nystagmus (1 pt), which together are highly specific for RPE65-related recessive retinopathy (9 total points, PMID: 31925606, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PMID: 31925606, PP1_Moderate). The computational predictor REVEL gives a score of 0.852, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.22, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥ 0.2 and predicts a damaging impact on splicing. Another missense variant in the same codon, NM_000329.3(RPE65):c.272G>A (p.Arg91Gln), has been classified as pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5). Splicing predictions using SpliceAI are equivalent for both of these variants. The variant exhibited 0% 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 (PMID: 16754667, PS3_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: PM2_Supporting, PM3_strong, PP4_moderate, PP1_moderate, PP3_moderate, PM5, and PS3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

Autosomal recessive retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Faculty of Health Sciences, Beirut Arab University

Nov 22, 2016

- -

Abnormality of the eye

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Leber congenital amaurosis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Leber congenital amaurosis;C3151086:Retinitis pigmentosa 20;CN239301:RPE65-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

The RPE65 c.271C>T (p.R91W) variant has been reported in the homozygous or compound heterozygous state in individuals with Leber congenital amaurosis, retinitis pigmentosa, or inherited retinal degeneration (PMID: 9501220; 10937591; 11095629; 18682808; 19117922; 21153841). -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jun 15, 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

0.89

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.86

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.85

Sift

Uncertain

0.012

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.94

MVP

1.0

MPC

0.36

ClinPred

0.78

GERP RS

4.0

Varity_R

0.63

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.22

Position offset: 25

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