rs1169420841

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_SupportingPM3_StrongPP3PP4

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.982C>T (p.Leu328Phe) variant is a missense variant causing a substitution of leucine with phenylalanine at position 328. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000003650, with 2/91076 in the South Asian population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.737, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.644 and predicts a damaging effect on RPE65 function (PP3). This variant has been reported in at least 4 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the p.Tyr275Ter variant confirmed in trans (Pathogenic by VCEP, 1 point, PMID:31630094); the NM_000329.3(RPE65):c.639dup (p.Ala214SerfsTer20) variant suspected in trans (Pathogenic by VCEP, 0.5 pt, PMID:28393863); the p.Glu254Asp variant suspected in trans (LP by VCEP, 0.25 pt, PMID:35129589 with additional information presented in ARVO meeting abstract https://iovs.arvojournals.org/article.aspx?articleid=2767855); or the p.Leu447Pro variant confirmed in trans (VUS by VCEP, 0.25 pt, PMID:38002999), all of which were previously classified as described above by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt), congenital night blindness (0.5 pt), White/yellow dot deposits (2 pt), previous exome testing that did not provide an alternative explanation for visual impairment (2 pt), and symptomatic onset between birth and 5 years (1 pt), which together are specific for RPE65-related recessive retinopathy (6 points, PMIDs: 31630094, 34830511, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3, PP4, PM3_Strong (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA340744630/MONDO:0100368/120

Frequency

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

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RPE65
NM_000329.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:4U:1

Conservation

PhyloP100: 6.32

Publications

8 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: Likely_pathogenic. The variant received 7 ACMG points.

PM2

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

PM3

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

PP3

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.982C>T	p.Leu328Phe	missense_variant	Exon 9 of 14	ENST00000262340.6	NP_000320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6 link	c.982C>T	p.Leu328Phe	missense_variant	Exon 9 of 14	1	NM_000329.3	ENSP00000262340.5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251398

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000274

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111936

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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:

0.00000657

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000487

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20

Pathogenic:1Uncertain:1

Jan 16, 2018

Counsyl

Significance:Uncertain significance

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.

Jun 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 328 of the RPE65 protein (p.Leu328Phe). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive early onset retinal dystrophy (PMID: 28393863, 31630094, 35129589). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 556178). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RPE65 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

RPE65-related recessive retinopathy

Pathogenic:1

Dec 12, 2024

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

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000329.3(RPE65):c.982C>T (p.Leu328Phe) variant is a missense variant causing a substitution of leucine with phenylalanine at position 328. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000003650, with 2/91076 in the South Asian population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.737, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.644 and predicts a damaging effect on RPE65 function (PP3). This variant has been reported in at least 4 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the p.Tyr275Ter variant confirmed in trans (Pathogenic by VCEP, 1 point, PMID: 31630094); the NM_000329.3(RPE65):c.639dup (p.Ala214SerfsTer20) variant suspected in trans (Pathogenic by VCEP, 0.5 pt, PMID: 28393863); the p.Glu254Asp variant suspected in trans (LP by VCEP, 0.25 pt, PMID: 35129589 with additional information presented in ARVO meeting abstract https://iovs.arvojournals.org/article.aspx?articleid=2767855); or the p.Leu447Pro variant confirmed in trans (VUS by VCEP, 0.25 pt, PMID: 38002999), all of which were previously classified as described above by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt), congenital night blindness (0.5 pt), White/yellow dot deposits (2 pt), previous exome testing that did not provide an alternative explanation for visual impairment (2 pt), and symptomatic onset between birth and 5 years (1 pt), which together are specific for RPE65-related recessive retinopathy (6 points, PMIDs: 31630094, 34830511, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3, PP4, PM3_Strong (VCEP specifications version 1.0.0; date of approval 09/21/2023).

not provided

Pathogenic:1

Jul 15, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34830511, 35129589, 36460718, 28393863, 33952291, 31273949, 29681726, 38002999, 31630094, Brunetti-Pierri 2020[Abstract], 38219857)

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

Pathogenic:1

Mar 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.86

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.0

PhyloP100

6.3

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0090

Vest4

0.75

ClinPred

0.99

GERP RS

4.9

Varity_R

0.61

gMVP

0.89

Mutation Taster

=16/84

disease causing

(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

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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