chr1-68438977-A-C

Position:

chr1-68438977-A-C

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -10 ACMG points.

BP4

BS3

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPE65	NM_000329.3 linkuse as main transcript	c.963T>G	p.Asn321Lys	missense_variant	9/14	ENST00000262340.6
LOC124904198	XR_007066164.1 linkuse as main transcript	n.72-9555A>C		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.963T>G	p.Asn321Lys	missense_variant	9/14	1	NM_000329.3	P1

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

GnomAD3 exomes

AF:

0.00516

AC:

1296

AN:

251376

Hom.:

AF XY:

0.00708

AC XY:

962

AN XY:

135848

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 SAS exome

AF:

0.0347

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

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.00429

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0357

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000539

Gnomad4 OTH exome

AF:

0.00260

GnomAD4 genome

AF:

0.00143

AC:

218

AN:

152276

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0280

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00111

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2022	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RPE65: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Leber congenital amaurosis 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, reviewed by expert panel

curation

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

Dec 22, 2023

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Leber congenital amaurosis

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 03, 2020

- -

Joubert syndrome 9

Benign:1

Benign, criteria provided, single submitter

research

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

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

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

MutationTaster

Benign

1.0

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

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