1-68439059-T-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PP3_ModerateBA1

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.881A>C is a missense variant that causes substitution of lysine with threonine at position 294. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.03554, with 1312 alleles / 35390 total alleles in the Admixed American population (with 33 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state (PMID:19431183) with the NM_000329.3(RPE65):c.1078G>C (p.Ala360Pro) variant in trans and a 22-bp deletion within exon 12 in cis (PMID:19431183). However, the proband was not counted for the PM3 or BP2 codes because the other two variants have not yet been classified by the ClinGen LCA / eoRD VCEP. The meta-predictor REVEL gives a score of 0.974, which is above the ClinGen LCA/eoRP VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 16%-68% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is between the ClinGen LCA / eoRD VCEP thresholds of <10% activity (PS3_Supporting) and >50% activity (BS3_Supporting), so neither functional study code is met (PMID:16150724, PMID:19431183). Another missense variant in the same codon, NM_000329.2; c.880A>G, (p.Lys294Glu), has been observed in a proband with early-onset severe retinal dystrophy (VCEP member-provided data), but has been classified as a variant of uncertain significance for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP, so the PM5_Supporting code is not met. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BA1 and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA146043/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.0025 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 38 hom. )

Consequence

RPE65
NM_000329.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:12O:1

Conservation

PhyloP100: 7.67

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_benign. Variant got -6 ACMG points.

PP3

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

BA1

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.881A>C	p.Lys294Thr	missense_variant	Exon 9 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.881A>C	p.Lys294Thr	missense_variant	Exon 9 of 14	1	NM_000329.3	ENSP00000262340.5		Q16518

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

378

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0225

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00527

AC:

1325

AN:

251234

Hom.:

AF XY:

0.00387

AC XY:

525

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0372

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00539

GnomAD4 exome

AF:

0.00119

AC:

1737

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

727

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0365

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00248

AC:

378

AN:

152288

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.0224

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.000733

Hom.:

Bravo

AF:

0.00569

ExAC

AF:

0.00400

AC:

486

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

May 03, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2Other:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RPE65: BS1, BS2 -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RPE65-related recessive retinopathy

Benign:1

Feb 20, 2024

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

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_000329.3(RPE65):c.881A>C is a missense variant that causes substitution of lysine with threonine at position 294. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.03554, with 1312 alleles / 35390 total alleles in the Admixed American population (with 33 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state (PMID: 19431183) with the NM_000329.3(RPE65):c.1078G>C (p.Ala360Pro) variant in trans and a 22-bp deletion within exon 12 in cis (PMID: 19431183). However, the proband was not counted for the PM3 or BP2 codes because the other two variants have not yet been classified by the ClinGen LCA / eoRD VCEP. The meta-predictor REVEL gives a score of 0.974, which is above the ClinGen LCA/eoRP VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 16%-68% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is between the ClinGen LCA / eoRD VCEP thresholds of <10% activity (PS3_Supporting) and >50% activity (BS3_Supporting), so neither functional study code is met (PMID: 16150724, PMID: 19431183). Another missense variant in the same codon, NM_000329.2; c.880A>G, (p.Lys294Glu), has been observed in a proband with early-onset severe retinal dystrophy (VCEP member-provided data), but has been classified as a variant of uncertain significance for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP, so the PM5_Supporting code is not met. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BA1 and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

Leber congenital amaurosis

Benign:1

Jun 18, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Leber congenital amaurosis 2

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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

Benign:1

Aug 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0088

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.92

MVP

1.0

MPC

0.38

ClinPred

0.10

GERP RS

5.2

Varity_R

0.92

gMVP

0.96

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

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