rs149916178

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BS3_SupportingBP4BA1

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.963T>G (p.Asn321Lys) missense variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.03299, with 1063 alleles / 30614 total alleles in the South Asian population with 29 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). This variant has been reported in at least one LCA patient, however the phenotype is not sufficiently specific to RPE65 and no second variant was described in trans, instead two CRB1 variants were identified (PMID:18055816). The computational predictor REVEL gives a score of 0.215, which is below the ClinGen LCA/eoRD VCEP threshold of <0.3 and predicts no damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). The variant exhibited 127% enzymatic activity in an isomerohydrolase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it preserves normal protein function (PMID:19431183, BS3). 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, BS3_Supporting, BP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA146044/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.0014 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 94 hom. )

Consequence

RPE65
NM_000329.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:11

Conservation

PhyloP100: 0.135

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

retinitis pigmentosa
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
Leber congenital amaurosis 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
RPE65-related recessive retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
RPE65-related dominant retinopathy
Inheritance: AD Classification: STRONG Submitted by: ClinGen
retinitis pigmentosa 20
Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe early-childhood-onset retinal dystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa 87 with choroidal involvement
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RPE65 links:

LOC124904198 (HGNC:):

LOC124904198 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

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

BS3

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

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.963T>G	p.Asn321Lys	missense_variant	Exon 9 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.963T>G	p.Asn321Lys	missense_variant	Exon 9 of 14	1	NM_000329.3	ENSP00000262340.5		Q16518

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

217

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0276

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00516

AC:

1296

AN:

251376

AF XY:

0.00708

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00476

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00277

AC:

4051

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00394

AC XY:

2864

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33476

American (AMR)

AF:

0.00107

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00429

AC:

112

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.0357

AC:

3076

AN:

86254

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00902

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000539

AC:

599

AN:

1111940

Other (OTH)

AF:

0.00260

AC:

157

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

283

567

850

1134

1417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00143

AC:

218

AN:

152276

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41546

American (AMR)

AF:

0.000785

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0280

AC:

135

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68030

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.000854

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00536

AC:

651

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00224

EpiControl

AF:

0.00160

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 08, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 17, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RPE65: BS1, BS2 -

Leber congenital amaurosis 2

Benign:2

May 18, 2021

Pars Genome Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Retinitis pigmentosa

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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(RPE65):c.963T>G (p.Asn321Lys) missense variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.03299, with 1063 alleles / 30614 total alleles in the South Asian population with 29 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). This variant has been reported in at least one LCA patient, however the phenotype is not sufficiently specific to RPE65 and no second variant was described in trans, instead two CRB1 variants were identified (PMID: 18055816). The computational predictor REVEL gives a score of 0.215, which is below the ClinGen LCA/eoRD VCEP threshold of <0.3 and predicts no damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). The variant exhibited 127% enzymatic activity in an isomerohydrolase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it preserves normal protein function (PMID: 19431183, BS3). 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, BS3_Supporting, BP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20

Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis

Benign:1

Apr 03, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joubert syndrome 9

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Asn321Lys variant in RPE65 has been identified in an individual with Leber congenital amaurosis (PMID: 10766140), but has also been identified in >3% of South Asian chromosomes and 18 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Leber congenital amaurosis. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.73

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.6

PhyloP100

0.14

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.3

REVEL

Benign

0.21

Sift

Benign

0.075

Sift4G

Benign

0.15

Polyphen

0.013

Vest4

0.42

MutPred

0.83

Gain of solvent accessibility (P = 0.0221);

MVP

0.78

MPC

0.064

ClinPred

0.0081

GERP RS

-0.30

Varity_R

0.19

gMVP

0.59

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over