rs61752895

Positions:

chr1-68439586-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4_ModeratePVS1PP1PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) is a nonsense variant that introduces a premature stop codon in exon 7 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). At least 6 probands have been reported with this variant, one of whom displayed nystagmus (1 pt), night blindness (0.5 pts), reduced visual acuity (1 pt), narrowing of retinal vessels (0.5 pts), moderate pallor of the optic discs (0.5 pts), difficulty discriminating any color (1 pt), unrecordable ERG (0.5 pts), absent autofluorescence (2 pts), and onset at birth (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total pts, PMIDs: 9326927, PMID:11264131 PMID:15288992, PP4_moderate). Additionally, the variant has been reported to segregate with the phenotype (confirmed by absent ERG) in the proband plus one similarly affected sibling harboring the variant in the compound heterozygous state (PP1; PMID:9326927). PM3 was not considered to avoid circularity, despite the presence of compound heterozygous cases harboring this variant as well as the p.Asn356fs, c.991_993dup (p.Trp331dup), or p.Arg124Ter variant. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002299, with 3 alleles / 34580 total alleles in the Admixed American 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: PVS1, PP4_Moderate, PM2_Supporting, and PP1. (VCEP specifications version 1.0.0; date of approval 09/21/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA226577/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

RPE65
ENST00000262340.6 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8O:1

Conservation

PhyloP100: 5.36

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 12 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

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
RPE65	NM_000329.3 linkuse as main transcript	c.700C>T	p.Arg234Ter	stop_gained	7/14	ENST00000262340.6	NP_000320.1
LOC124904198	XR_007066164.1 linkuse as main transcript	n.72-8946G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6 linkuse as main transcript	c.700C>T	p.Arg234Ter	stop_gained	7/14	1	NM_000329.3	ENSP00000262340	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251384

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461614

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000445

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

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	Oct 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -

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

Dec 22, 2023

NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) is a nonsense variant that introduces a premature stop codon in exon 7 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). At least 6 probands have been reported with this variant, one of whom displayed nystagmus (1 pt), night blindness (0.5 pts), reduced visual acuity (1 pt), narrowing of retinal vessels (0.5 pts), moderate pallor of the optic discs (0.5 pts), difficulty discriminating any color (1 pt), unrecordable ERG (0.5 pts), absent autofluorescence (2 pts), and onset at birth (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total pts, PMIDs: 9326927, PMID: 11264131 PMID: 15288992, PP4_moderate). Additionally, the variant has been reported to segregate with the phenotype (confirmed by absent ERG) in the proband plus one similarly affected sibling harboring the variant in the compound heterozygous state (PP1; PMID: 9326927). PM3 was not considered to avoid circularity, despite the presence of compound heterozygous cases harboring this variant as well as the p.Asn356fs, c.991_993dup (p.Trp331dup), or p.Arg124Ter variant. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002299, with 3 alleles / 34580 total alleles in the Admixed American 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: PVS1, PP4_Moderate, PM2_Supporting, and PP1. (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

Dec 27, 2023

This sequence change creates a premature translational stop signal (p.Arg234*) in the RPE65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 9843205, 18632300). This variant is present in population databases (rs61752895, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with inherited retinal dystrophy (PMID: 9326927, 30268864). 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: 13114). 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

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 20, 2020

- -

Retinitis pigmentosa 20

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ocular Genomics Institute, Massachusetts Eye and Ear

Apr 08, 2021

The RPE65 c.700C>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: PP1-M, PM2, PVS1. Based on this evidence we have classified this variant as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

May 27, 2024

- -

not provided

Other:1

not provided, no classification provided

literature only

Retina International

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

Vest4

0.97

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.24

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