chr1-68431319-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2BA1BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.1301C>T (p.Ala434Val) missense variant that is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.07646, with 1976 alleles / 24962 total alleles in the African / African-American population with 72 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant has been reported in at least one patient with retinal dystrophy, however the phenotype is not specific to RPE65 and no second variant was described in trans (PMID:9501220). Three separate publications on families who carry this variant have reported unaffected individuals who harbor it in homozygous state (PMID:19431183, PMID:9501220, PMID:19920137, BS2). The computational predictor REVEL gives a score of 0.418, which is below the ClinGen LCA / eoRD VCEP threshold of ≥ 0.7 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.14, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. The variant exhibited 110% or 55% enzymatic activity in two retinoid isomerase assays relative to the wild-type control, which are higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves normal protein function (PMID:19431183, PMID:16150724, BS3_Supporting). 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, BS2, BS3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226501/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.022 ( 109 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 113 hom. )

Consequence

RPE65
NM_000329.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:12O:1

Conservation

PhyloP100: 7.38

Publications

12 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 -13 ACMG points.

BS2

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.1301C>T	p.Ala434Val	missense_variant	Exon 12 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.1301C>T	p.Ala434Val	missense_variant	Exon 12 of 14	1	NM_000329.3	ENSP00000262340.5		Q16518

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3353

AN:

152152

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0774

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00694

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00574

AC:

1441

AN:

250840

AF XY:

0.00412

show subpopulations

Gnomad AFR exome

AF:

0.0801

Gnomad AMR exome

AF:

0.00313

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00210

AC:

3065

AN:

1461654

Hom.:

113

Cov.:

AF XY:

0.00178

AC XY:

1293

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.0771

AC:

2579

AN:

33462

American (AMR)

AF:

0.00360

AC:

161

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000432

AC:

AN:

1111886

Other (OTH)

AF:

0.00431

AC:

260

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

175

350

525

700

875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<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:

0.0220

AC:

3349

AN:

152268

Hom.:

109

Cov.:

AF XY:

0.0205

AC XY:

1530

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0770

AC:

3200

AN:

41536

American (AMR)

AF:

0.00693

AC:

106

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68032

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

168

336

505

673

841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.00946

Hom.:

200

Bravo

AF:

0.0240

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0751

AC:

331

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00697

AC:

846

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 14, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 30, 2016

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. -

Dec 10, 2021

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:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 16, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2017

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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.1301C>T (p.Ala434Val) missense variant that is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.07646, with 1976 alleles / 24962 total alleles in the African / African-American population with 72 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant has been reported in at least one patient with retinal dystrophy, however the phenotype is not specific to RPE65 and no second variant was described in trans (PMID: 9501220). Three separate publications on families who carry this variant have reported unaffected individuals who harbor it in homozygous state (PMID: 19431183, PMID: 9501220, PMID: 19920137, BS2). The computational predictor REVEL gives a score of 0.418, which is below the ClinGen LCA / eoRD VCEP threshold of greater than or equal to 0.7 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.14, which is below the ClinGen LCA / eoRD VCEP recommended threshold of greater than or equal to 0.2 and does not strongly predict an impact on splicing. The variant exhibited 110% or 55% enzymatic activity in two retinoid isomerase assays relative to the wild-type control, which are higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves normal protein function (PMID: 19431183, PMID: 16150724, BS3_Supporting). 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, BS2, BS3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

Leber congenital amaurosis

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Leber congenital amaurosis 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20;C5231465:Retinitis pigmentosa 87 with choroidal involvement

Benign:1

Apr 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.13

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.26

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0060

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

0.94

PhyloP100

7.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.92

REVEL

Uncertain

0.42

Sift

Benign

1.0

Sift4G

Benign

0.67

Polyphen

0.026

Vest4

0.54

MVP

0.96

MPC

0.056

ClinPred

0.041

GERP RS

5.1

Varity_R

0.14

gMVP

0.52

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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