dbSNP rs1191496583: RPE65:p.Gly140Glu (chr1-68444607-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_SupportingPM3_StrongPP3_ModeratePP4_Moderate

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.419G>A is a missense variant causing substitution of glycine by glutamic acid at position 140. This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID:30870047). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.242G>T (p.Arg81Ile) and NM_000329.3(RPE65):c.1338G>T (p.Arg446Ser) variants confirmed in trans (2 points, PMID:30870047), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis with Leber congenital amaurosis (0.5 pts) by exome sequencing that did not provide an alternative explanation for visual impairment (2 pts), onset at 1 month of age (1 pt), undetectable ERG responses from rods (0.5 pts) and cones (1 pt), nyctalopia (0.5 pts), reduced visual acuity (1 pt), light gazing (1 pt), RPE mottling (0.5 pts), optic nerve pallor (0.5 pt), nystagmus (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt), which together are highly specific for RPE65-related recessive retinopathy (10 total points, PMID:30870047, PP4_Moderate). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00003893, with 5 alleles / 35438 total alleles in the Admixed American 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 0.847, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). 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, PM3_Strong, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA340747862/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.00012 ( 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:4

Conservation

PhyloP100: 7.39

Publications

0 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 9 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.

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.419G>A	p.Gly140Glu	missense	Exon 5 of 14	NP_000320.1
RPE65	NM_001406853.1		c.311G>A	p.Gly104Glu	missense	Exon 4 of 13	NP_001393782.1
RPE65	NM_001406856.1		c.143G>A	p.Gly48Glu	missense	Exon 4 of 13	NP_001393785.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPE65	ENST00000262340.6	TSL:1 MANE Select	c.419G>A	p.Gly140Glu	missense	Exon 5 of 14	ENSP00000262340.5
RPE65	ENST00000713936.1		n.*324G>A		non_coding_transcript_exon	Exon 6 of 15	ENSP00000519233.1
RPE65	ENST00000713937.1		n.419G>A		non_coding_transcript_exon	Exon 5 of 13	ENSP00000519234.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.0000159

AC:

AN:

251412

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000125

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41404

American (AMR)

AF:

0.00124

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

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:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000102

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RPE65-related recessive retinopathy

Pathogenic:1

Feb 01, 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

NM_000329.3(RPE65):c.419G>A is a missense variant causing substitution of glycine by glutamic acid at position 140. This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 30870047). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.242G>T (p.Arg81Ile) and NM_000329.3(RPE65):c.1338G>T (p.Arg446Ser) variants confirmed in trans (2 points, PMID: 30870047), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis with Leber congenital amaurosis (0.5 pts) by exome sequencing that did not provide an alternative explanation for visual impairment (2 pts), onset at 1 month of age (1 pt), undetectable ERG responses from rods (0.5 pts) and cones (1 pt), nyctalopia (0.5 pts), reduced visual acuity (1 pt), light gazing (1 pt), RPE mottling (0.5 pts), optic nerve pallor (0.5 pt), nystagmus (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt), which together are highly specific for RPE65-related recessive retinopathy (10 total points, PMID: 30870047, PP4_Moderate). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00003893, with 5 alleles / 35438 total alleles in the Admixed American 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 0.847, which is above the ClinGen LCA / eoRD VCEP threshold of >= 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). 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, PM3_Strong, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20

Pathogenic:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 140 of the RPE65 protein (p.Gly140Glu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with Leber congenital amaurosis or retinitis pigmentosa (PMID: 28181551, 30870047). 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: 467827). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Leber congenital amaurosis

Pathogenic:1

Jun 01, 2018

Cytogenetics and Genomics Laboratory, Medical University of South Carolina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Leber congenital amaurosis 2

Pathogenic:1

Oct 23, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.2

PhyloP100

7.4

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0080

Sift4G

Benign

0.075

Polyphen

0.93

Vest4

0.98

MutPred

0.58

Loss of sheet (P = 0.1398)

MVP

1.0

MPC

0.39

ClinPred

0.95

GERP RS

5.0

Varity_R

0.75

gMVP

0.86

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over