rs61752909

Positions:

• chr1-68438293-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4_Moderate PM2_Supporting PM3_Strong PP1_Strong PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) missense variant replaces the leucine at position 341 with serine and has been reported in several patients. At least one patient (analyzed on a 100+ retinal dystrophy gene panel testing (2 pt) in PMID:23847139) who displayed a non-detectable ERG (2 pt), visual acuity 20/400 OD and OS (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (1 pt), and no pigment in peripheral retina, which is highly specific for RPE65 retinopathy (PP4_Moderate). One patient was compound heterozygous for this variant and a pathogenic pathogenic variant (c.1205_1206insCCTG classified Pathogenic by the LCA/eoRD VCEP) confirmed in trans by parental testing (PMID:9501220) and two probands were homozygous for the variant (PMID:9501220, PMID:15837919) (PM3_strong). The variant has been reported to segregate with RPE65 retinopathy (confirmed by absent or severely decreased rod electroretinogram response) in the proband plus 3 affected family members, all with the compound heterozygous genotype of Leu341Ser and c.1205_1206insCCTG variants. (PP1_strong; PMID:9501220). The computational predictor REVEL gives a score of 0.988 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is absent from gnomAD v2.1.1 and has a Grpmax Filtering AF of 0.00005290 in gnomAD v.3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP1_strong, PM3_strong, PP3_Moderate, PP4_Moderate, PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226472/MONDO:0100368/120

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RPE65 NM_000329.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14 O:1
• Conservation: PhyloP100: 8.84

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]

LOC124904198 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 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.
• PP1: 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	c.1022T>C	p.Leu341Ser	missense_variant	10/14	ENST00000262340.6	NP_000320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6	c.1022T>C	p.Leu341Ser	missense_variant	10/14	1	NM_000329.3	ENSP00000262340.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461324 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber congenital amaurosis 2 Pathogenic:4

Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013118). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 20079931) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:9501220). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Leber congenital amaurosis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 14, 2024	Variant summary: RPE65 c.1022T>C (p.Leu341Ser) 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 was absent in 250484 control chromosomes. c.1022T>C has been reported in the literature in multiple individuals affected with Retinitis pigmentosa (Morimura_1998). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 9501220). ClinVar contains an entry for this variant (Variation ID: 13118). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 18, 2020	- -
Likely pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	Jul 24, 2023	Clinical significance based on ACMG v2.0 -

Retinitis pigmentosa 20 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 05, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 17, 1998	- -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2021	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32865313, 32036094, 19854499, 21862650, 19753312, 30268864, 9501220, 29186038, 20079931, 20683928, 20811047, 27375040, 19117922, 18539930, 21153841, 10800710, 17964524) -

RPE65-related recessive retinopathy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

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

Feb 20, 2024

The NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) missense variant replaces the leucine at position 341 with serine and has been reported in several patients. At least one patient (analyzed on a 100+ retinal dystrophy gene panel testing (2 pt) in PMID: 23847139) who displayed a non-detectable ERG (2 pt), visual acuity 20/400 OD and OS (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (1 pt), and no pigment in peripheral retina, which is highly specific for RPE65 retinopathy (PP4_Moderate). One patient was compound heterozygous for this variant and a pathogenic pathogenic variant (c.1205_1206insCCTG classified Pathogenic by the LCA/eoRD VCEP) confirmed in trans by parental testing (PMID: 9501220) and two probands were homozygous for the variant (PMID: 9501220, PMID: 15837919) (PM3_strong). The variant has been reported to segregate with RPE65 retinopathy (confirmed by absent or severely decreased rod electroretinogram response) in the proband plus 3 affected family members, all with the compound heterozygous genotype of Leu341Ser and c.1205_1206insCCTG variants. (PP1_strong; PMID: 9501220). The computational predictor REVEL gives a score of 0.988 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is absent from gnomAD v2.1.1 and has a Grpmax Filtering AF of 0.00005290 in gnomAD v.3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP1_strong, PM3_strong, PP3_Moderate, PP4_Moderate, PM2_supporting. (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

Jan 28, 2024

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 341 of the RPE65 protein (p.Leu341Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Leber congenital amaurosis or retinitis pigmentosa (PMID: 9501220, 18539930, 19854499, 20079931, 20683928). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13118). 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 95%. For these reasons, this variant has been classified as Pathogenic. -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20;C5231465:Retinitis pigmentosa 87 with choroidal involvement Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.88
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.83		Gain of catalytic residue at L341 (P = 0.0097);
MVP		0.99
MPC		0.41
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.68
gMVP		0.94

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

Other links and lift over

dbSNP: rs61752909; hg19: chr1-68903976;