1-68431559-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7BP4BA1

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.1155G>A (p.Thr385=) is a synonymous variant at codon 385. The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01596, with 704 alleles / 41408 total alleles in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). 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, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226488/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.0056 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 8 hom. )

Consequence

RPE65
NM_000329.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:10O:1

Conservation

PhyloP100: -1.47

Publications

2 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.

BP7

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

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000329.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPE65	NM_000329.3	MANE Select	c.1155G>A	p.Thr385Thr	synonymous	Exon 11 of 14	NP_000320.1
RPE65	NM_001406853.1		c.1047G>A	p.Thr349Thr	synonymous	Exon 10 of 13	NP_001393782.1
RPE65	NM_001406856.1		c.879G>A	p.Thr293Thr	synonymous	Exon 10 of 13	NP_001393785.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPE65	ENST00000262340.6	TSL:1 MANE Select	c.1155G>A	p.Thr385Thr	synonymous	Exon 11 of 14	ENSP00000262340.5
RPE65	ENST00000713936.1		n.*1060G>A		non_coding_transcript_exon	Exon 12 of 15	ENSP00000519233.1
RPE65	ENST00000713937.1		n.*209G>A		non_coding_transcript_exon	Exon 11 of 13	ENSP00000519234.1

Frequencies

GnomAD3 genomes

AF:

0.00561

AC:

854

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0170

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00200

AC:

502

AN:

250418

AF XY:

0.00182

show subpopulations

Gnomad AFR exome

AF:

0.0162

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00259

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000895

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00111

AC:

1621

AN:

1461586

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

775

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.0191

AC:

638

AN:

33460

American (AMR)

AF:

0.00255

AC:

114

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00272

AC:

AN:

26124

East Asian (EAS)

AF:

0.000277

AC:

AN:

39692

South Asian (SAS)

AF:

0.000522

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00711

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000490

AC:

545

AN:

1111830

Other (OTH)

AF:

0.00252

AC:

152

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

187

280

374

467

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00562

AC:

855

AN:

152222

Hom.:

Cov.:

AF XY:

0.00568

AC XY:

423

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0170

AC:

705

AN:

41530

American (AMR)

AF:

0.00556

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00166

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

68026

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

126

168

210

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:

0.00231

Hom.:

Bravo

AF:

0.00650

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Mar 03, 2015

GeneDx

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

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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 16, 2017

Counsyl

Significance:Likely 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.

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

NM_000329.3(RPE65):c.1155G>A (p.Thr385=) is a synonymous variant at codon 385. The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01596, with 704 alleles / 41408 total alleles in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). 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, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Leber congenital amaurosis 2

Benign:1

Sep 15, 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

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinitis pigmentosa

Benign:1

Sep 15, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.079

(source)

DANN

Benign

0.45

PhyloP100

-1.5

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over