rs62642583

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_SupportingPVS1PM3

This summary comes from the ClinGen Evidence Repository: NM_000329.2(RPE65):c.292_311del (p.Ile98Hisfs) is a deletion variant in exon 4 of 14 that causes a frameshift and introduces a premature stop after 26 codons. This frameshift is predicted to trigger nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). A number of affected patients have been reported harboring this variant, including at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID:30870047, PM3). This variant has a Grpmax filtering allele frequency of 0.0001565 (10/34580) in the Latino / Admixed American population in gnomAD v2.1.1 (with no homozygotes). This allele frequency is lower than the ClinGen LCA/eoRD VCEP threshold (<0.0002) (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, PM3, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226536/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

RPE65
NM_000329.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:9O:1

Conservation

PhyloP100: 9.37

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.

PM3

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.292_311delATCGTCATAACAGAATTTGG	p.Ile98HisfsTer26	frameshift_variant	Exon 4 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.292_311delATCGTCATAACAGAATTTGG	p.Ile98HisfsTer26	frameshift_variant	Exon 4 of 14	1	NM_000329.3	ENSP00000262340.5		Q16518

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

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

GnomAD2 exomes

AF:

0.0000438

AC:

AN:

251352

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461864

Hom.:

AF XY:

0.00000963

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111998

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

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:

0.000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000117

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Leber congenital amaurosis

Pathogenic:2

Jan 06, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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:2

Aug 10, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 13, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32865313, 31589614, 30870047, 10766140, 28181551) -

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

NM_000329.2(RPE65):c.292_311del (p.Ile98Hisfs) is a deletion variant in exon 4 of 14 that causes a frameshift and introduces a premature stop after 26 codons. This frameshift is predicted to trigger nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). A number of affected patients have been reported harboring this variant, including at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 30870047, PM3). This variant has a Grpmax filtering allele frequency of 0.0001565 (10/34580) in the Latino / Admixed American population in gnomAD v2.1.1 (with no homozygotes). This allele frequency is lower than the ClinGen LCA/eoRD VCEP threshold (<0.0002) (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, PM3, 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

Feb 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ile98Hisfs*26) in the RPE65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 9843205, 18632300). This variant is present in population databases (rs767212885, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with RPE65-related conditions (PMID: 10766140, 28181551). ClinVar contains an entry for this variant (Variation ID: 98860). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

May 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 20

Pathogenic:1

Feb 01, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000098860 /PMID: 10766140, 32347917, 35129589 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.4

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over