chr1-68429781-A-T

Position:

chr1-68429781-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000329.3:c.1597T>A is a missense variant in RPE65 causing substitution of serine with threonine at position 533. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002596, with 3 alleles / 30608 total alleles 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 0.568, which is below the ClinGen LCA / eoRD VCEP threshold of ≥ 0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00 for all change types, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis, however other available phenotypes are not sufficient to evaluate specificity for RPE65-related recessive retinopathy and no second variant has been identified, so PP4 is not met (PMID:17964524). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID:25097241). However, the proband was not counted for PM3_Supporting because the NM_000329.3(RPE65):c.89T>C (p.Val30Ala) variant suspected in trans has not yet been classified for RPE65-related recessive retinopathy and because sufficient phenotype information was not available. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA902125/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

RPE65
NM_000329.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:6

Conservation

PhyloP100: 1.45

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

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.1597T>A	p.Ser533Thr	missense_variant	14/14	ENST00000262340.6	NP_000320.1
LOC124904198	XR_007066164.1 linkuse as main transcript	n.71+9660A>T		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.1597T>A	p.Ser533Thr	missense_variant	14/14	1	NM_000329.3	ENSP00000262340	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152046

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250456

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135386

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:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461312

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726956

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:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 28, 2021

Variant summary: RPE65 c.1597T>A (p.Ser533Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1597T>A has been reported in the literature as a compound heterozygous genotype in at-least one individual from a cohort of non-syndromic Retinitis Pigmentosa (example, Wang_2014) and as a non-informative genotype (second allele not specified) in at-least one individual affected with Leber Congenital Amaurosis (example, Stone_2007). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

RPE65-related recessive retinopathy

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Feb 18, 2024

NM_000329.3:c.1597T>A is a missense variant in RPE65 causing substitution of serine with threonine at position 533. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002596, with 3 alleles / 30608 total alleles 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 0.568, which is below the ClinGen LCA / eoRD VCEP threshold of >= 0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00 for all change types, which is below the ClinGen LCA / eoRD VCEP recommended threshold of >=0.2 and does not strongly predict an impact on splicing. At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis, however other available phenotypes are not sufficient to evaluate specificity for RPE65-related recessive retinopathy and no second variant has been identified, so PP4 is not met (PMID: 17964524). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 25097241). However, the proband was not counted for PM3_Supporting because the NM_000329.3(RPE65):c.89T>C (p.Val30Ala) variant suspected in trans has not yet been classified for RPE65-related recessive retinopathy and because sufficient phenotype information was not available. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2022

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 533 of the RPE65 protein (p.Ser533Thr). This variant is present in population databases (rs577335767, gnomAD 0.01%). This missense change has been observed in individual(s) with RPE65-related retinal dystrophy (PMID: 17964524, 25097241). ClinVar contains an entry for this variant (Variation ID: 870342). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Leber congenital amaurosis

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 20, 2020

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 27, 2022

- -

Leber congenital amaurosis 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

Feb 14, 2020

This variant is interpreted as a variant of uncertain significance for Leber congenital amaurosis 2, autosomal recessive. The following ACMG Tag(s) were applied: PM2, BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.29

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.74

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.090

MutationTaster

Benign

0.83

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.45

REVEL

Uncertain

0.57

Sift

Uncertain

0.023

Sift4G

Benign

0.16

Polyphen

0.0

Vest4

0.68

MutPred

0.78

Loss of glycosylation at S533 (P = 0.1279);

MVP

0.81

MPC

0.052

ClinPred

0.040

GERP RS

1.8

Varity_R

0.074

gMVP

0.61

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