1-68444664-GA-GAA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_SupportingPP4_ModeratePVS1

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.361dup (p.Ser121fs) frameshift variant introduces a premature stop codon in exon 5 of 14 and is predicted to trigger nonsense-mediated decay (PVS1). It is reported in the literature in a compound heterozygous state in at least one proband (by whole exome sequencing) who was diagnosed with Leber congenital amaurosis and exhibits infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), flat rod ERG (required, 1 pt), and flat cone ERG (1 pt), which together is highly specific for RPE65-related recessive retinopathy (PMID:30870047, PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP4_Moderate, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA23575009/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RPE65
NM_000329.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 2.74

Publications

4 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: Pathogenic. The variant received 11 ACMG points.

PVS1

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

PM2

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

PP4

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.361dupT	p.Ser121PhefsTer10	frameshift_variant	Exon 5 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.361dupT	p.Ser121PhefsTer10	frameshift_variant	Exon 5 of 14	1	NM_000329.3	ENSP00000262340.5		Q16518

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111994

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151926

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41360

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RPE65-related recessive retinopathy

Pathogenic:1

Feb 20, 2024

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

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000329.3(RPE65):c.361dup (p.Ser121fs) frameshift variant introduces a premature stop codon in exon 5 of 14 and is predicted to trigger nonsense-mediated decay (PVS1). It is reported in the literature in a compound heterozygous state in at least one proband (by whole exome sequencing) who was diagnosed with Leber congenital amaurosis and exhibits infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), flat rod ERG (required, 1 pt), and flat cone ERG (1 pt), which together is highly specific for RPE65-related recessive retinopathy (PMID: 30870047, PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP4_Moderate, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023) -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20

Pathogenic:1

May 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220). This variant has been observed in an individual affected with Leber's congenital amaurosis (PMID: 24066033). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser121Phefs*10) in the RPE65 gene. It is expected to result in an absent or disrupted protein product. -

Leber congenital amaurosis

Pathogenic:1

Jun 01, 2018

Cytogenetics and Genomics Laboratory, Medical University of South Carolina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Leber congenital amaurosis 2

Pathogenic:1

Jun 13, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.28

Position offset: 8

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