rs62636300

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM3_StrongPP3_ModeratePP4_ModeratePM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.1292A>G is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 431. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002, with 1/113326 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.907A>T (p.Lys303Ter) or c.1102T>C (p.Tyr368His) variants confirmed in trans (2 point, PMIDs: 14962443, 30268864), which were previously classified pathogenic 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 pts), absent or severely decreased rod electroretinogram responses (0.5 pts), congenital night blindness (0.5 pts), optic nerve pallor (0.5 pts), Pigmentary retinopathy with attenuated vessels (0.5 pts), macular atrophy (0.5 pts), symptomatic onset between birth and age five years (1 pt), decreased central visual acuity (1 pt), abnormal color vision or evidence of cone involvement on ERG (1 pt), nystagmus (1 pt), and significant improvement following gene therapy (8 pt) which together are highly specific for RPE65-related recessive retinopathy (PMIDs: 14962443, 19117922, 22323828, 15 points, PP4_Moderate). The computational predictor REVEL gives a score of 0.94, 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/eoRP VCEP: PM3_Strong, PP4_Moderate, PM2_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226500/MONDO:0100368/120

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

RPE65
ENST00000262340.6 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7O:1

Conservation

PhyloP100: 7.55

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 links:

LOC124904198 (HGNC:):

LOC124904198 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPE65	NM_000329.3 linkuse as main transcript	c.1292A>G	p.Tyr431Cys	missense_variant	12/14	ENST00000262340.6	NP_000320.1
LOC124904198	XR_007066164.1 linkuse as main transcript	n.71+11207T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6 linkuse as main transcript	c.1292A>G	p.Tyr431Cys	missense_variant	12/14	1	NM_000329.3	ENSP00000262340	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250892

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135552

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000479

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Leber congenital amaurosis 2

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 29, 2023	- -

not provided

Pathogenic:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30268864, 14962443) -
not provided, no classification provided	literature only	Retina International	-	- -

RPE65-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The RPE65 c.1292A>G variant is predicted to result in the amino acid substitution p.Tyr431Cys. This variant has been reported with a second RPE65 variant in several individuals with autosomal recessive Leber congenital amaurosis (Al-Khayer et al. 2004. PubMed ID: 14962443; Chung et al. 2018. PubMed ID: 30268864; Kumaran et al. 2018. PubMed ID: 30025081). The ClinGen Leber Congenital Amaurosis/Early Onset Retinal Dystrophy Variant Curation Expert Panel has also categorized this variant as likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/29873/). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

RPE65-related recessive retinopathy

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Jan 31, 2024

NM_000329.3(RPE65):c.1292A>G is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 431. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002, with 1/113326 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.907A>T (p.Lys303Ter) or c.1102T>C (p.Tyr368His) variants confirmed in trans (2 point, PMIDs: 14962443, 30268864), which were previously classified pathogenic 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 pts), absent or severely decreased rod electroretinogram responses (0.5 pts), congenital night blindness (0.5 pts), optic nerve pallor (0.5 pts), Pigmentary retinopathy with attenuated vessels (0.5 pts), macular atrophy (0.5 pts), symptomatic onset between birth and age five years (1 pt), decreased central visual acuity (1 pt), abnormal color vision or evidence of cone involvement on ERG (1 pt), nystagmus (1 pt), and significant improvement following gene therapy (8 pt) which together are highly specific for RPE65-related recessive retinopathy (PMIDs: 14962443, 19117922, 22323828, 15 points, PP4_Moderate). The computational predictor REVEL gives a score of 0.94, 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/eoRP VCEP: PM3_Strong, PP4_Moderate, PM2_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 431 of the RPE65 protein (p.Tyr431Cys). This variant is present in population databases (rs62636300, gnomAD 0.0009%). This missense change has been observed in individual(s) with Leber congenital amaurosis or clinical features of inherited retinal dystrophy (PMID: 14962443, 19117922, 30268864; Invitae). 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: 29873). 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 expected to disrupt RPE65 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Leber congenital amaurosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 28, 2023

Variant summary: RPE65 c.1292A>G (p.Tyr431Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250892 control chromosomes (gnomAD). c.1292A>G has been reported in the literature in individuals affected with Leber Congenital Amaurosis or inherited retinal dystrophy (examples: Al-Khayer_2004, Chung_2019, Kumaran_2020). Multiple reports have classified this variant as likely pathogenic (Hanany_2020 and Johnston_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15837919, 14962443, 19117922, 30268864, 31964843, 17964524, 34906458, 32347917, 30025081). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-8.1

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.96

MutPred

0.94

Gain of sheet (P = 0.0477);

MVP

1.0

MPC

0.39

ClinPred

1.0

GERP RS

5.1

Varity_R

0.83

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over