1-68438259-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000329.3:c.1056G>A variant is a synonymous variant in codon 352 of RPE65, and is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.3944, with 8033 alleles / 19884 total alleles in the East Asian population with 1627 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant does not have a strong prediction of impact at splicing sites according to SpliceAI, which calculates a delta score of 0.12 for splice acceptor gain. Because this score is higher than the ClinGen LCA / eoRD VCEP BP4 / BP7 threshold of <0.1 and lower than the PP3 threshold of >0.2, no in silico predictive codes are met. In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA285811/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.16 ( 2342 hom., cov: 32)

Exomes 𝑓: 0.13 ( 14595 hom. )

Consequence

RPE65
NM_000329.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:11O:1

Conservation

PhyloP100: 0.00100

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPE65	NM_000329.3 link	c.1056G>A	p.Glu352Glu	synonymous_variant	Exon 10 of 14	ENST00000262340.6	NP_000320.1	Q16518

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6 link	c.1056G>A	p.Glu352Glu	synonymous_variant	Exon 10 of 14	1	NM_000329.3	ENSP00000262340.5		Q16518

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

24502

AN:

151892

Hom.:

2339

Cov.:

show subpopulations

Gnomad AFR

AF:

0.227

Gnomad AMI

AF:

0.200

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.0900

Gnomad EAS

AF:

0.389

Gnomad SAS

AF:

0.195

Gnomad FIN

AF:

0.100

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.155

GnomAD3 exomes

AF:

0.154

AC:

38661

AN:

251046

Hom.:

3805

AF XY:

0.153

AC XY:

20811

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.231

Gnomad AMR exome

AF:

0.116

Gnomad ASJ exome

AF:

0.0908

Gnomad EAS exome

AF:

0.402

Gnomad SAS exome

AF:

0.190

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.121

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.132

AC:

192190

AN:

1461228

Hom.:

14595

Cov.:

AF XY:

0.132

AC XY:

96194

AN XY:

726940

show subpopulations

Gnomad4 AFR exome

AF:

0.228

Gnomad4 AMR exome

AF:

0.121

Gnomad4 ASJ exome

AF:

0.0906

Gnomad4 EAS exome

AF:

0.372

Gnomad4 SAS exome

AF:

0.185

Gnomad4 FIN exome

AF:

0.0996

Gnomad4 NFE exome

AF:

0.119

Gnomad4 OTH exome

AF:

0.140

GnomAD4 genome

AF:

0.161

AC:

24519

AN:

152010

Hom.:

2342

Cov.:

AF XY:

0.164

AC XY:

12171

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.227

Gnomad4 AMR

AF:

0.147

Gnomad4 ASJ

AF:

0.0900

Gnomad4 EAS

AF:

0.389

Gnomad4 SAS

AF:

0.193

Gnomad4 FIN

AF:

0.100

Gnomad4 NFE

AF:

0.118

Gnomad4 OTH

AF:

0.155

Alfa

AF:

0.130

Hom.:

1033

Bravo

AF:

0.167

Asia WGS

AF:

0.232

AC:

805

AN:

3478

EpiCase

AF:

0.121

EpiControl

AF:

0.117

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Leber congenital amaurosis 2

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1Other:1

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

RPE65-related recessive retinopathy

Benign:1

Dec 22, 2023

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000329.3:c.1056G>A variant is a synonymous variant in codon 352 of RPE65, and is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.3944, with 8033 alleles / 19884 total alleles in the East Asian population with 1627 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant does not have a strong prediction of impact at splicing sites according to SpliceAI, which calculates a delta score of 0.12 for splice acceptor gain. Because this score is higher than the ClinGen LCA / eoRD VCEP BP4 / BP7 threshold of <0.1 and lower than the PP3 threshold of >0.2, no in silico predictive codes are met. In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

Retinitis pigmentosa 87 with choroidal involvement

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis

Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Retinitis pigmentosa

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.6

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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