GeneBe

chr1-68431282-C-A

Position:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PP4_ModeratePVS1PP1PM2_SupportingPM3_Strong

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.1338G>T is a missense variant that substitutes arginine with serine at position 446. The variant is found in multiple probands affected with early-onset severe retinal dystrophy. At least one patient genotyped by whole exome sequencing (2 pts) has a diagnosis of Leber congenital amaurosis (0.5 pts) with infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), and flat rod (0.5 pts) and cone (1 pt) ERG responses, which together are highly specific for RPE65-related recessive retinopathy (9.5 pts, PMID:30870047, PP4_Moderate). At least 3 reported probands harbor the variant in the homozygous state, while an additional proband harbors this maternal variant in compound heterozygosity with a paternal c.361dup (p.Ser121Phefs*10 variant (previously classified pathogenic by the ClinGen LCA/eoRD VCEP)(PMID:30870047, PM3_Strong). Three pairs of siblings have been reported (PMID:30870047) harboring the variant in either the homozygous or compound heterozygous state (PP1). This variant has a Grpmax Filtering AF of 0.000009610 (2/34488, with no homozygotes) in the Latino/Admixed American population in gnomAD v2.1.1 which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002. Although the meta-predictor REVEL gives a score of 0.571, which is below the ClinGen LCA/eoRD VCEP PP3 threshold of >0.7, the computational splicing predictor SpliceAI indicates that the variant triggers the loss of a splice donor site, with a change score of 0.45. The variant was confirmed to exhibit a complete splicing defect in two minigene assays relative to the wild-type control, showing skipping of the 95-bp exon 12, indicating that it triggers nonsense-mediated decay (PMID:30996589, PMID:28714225, PVS1). 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: PVS1, PM2_Supporting, PM3_Strong, PP1, PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA340742354/MONDO:0100368/120

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RPE65
NM_000329.3 missense, splice_region

Scores

2
9
8
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 5.67
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
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.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RPE65NM_000329.3 linkuse as main transcriptc.1338G>T p.Arg446Ser missense_variant, splice_region_variant 12/14 ENST00000262340.6 NP_000320.1 Q16518

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RPE65ENST00000262340.6 linkuse as main transcriptc.1338G>T p.Arg446Ser missense_variant, splice_region_variant 12/141 NM_000329.3 ENSP00000262340.5 Q16518

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250622
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135426
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000580
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:
0.00
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461164
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726930
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000672
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
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
Bravo
AF:
0.0000491

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Leber congenital amaurosis Pathogenic:2
Likely pathogenic, criteria provided, single submitterresearchCytogenetics and Genomics Laboratory, Medical University of South CarolinaJun 01, 2018- -
Pathogenic, no assertion criteria providedresearchRui Chen Lab, Baylor College of MedicineMay 09, 2017- -
RPE65-related recessive retinopathy Pathogenic:1
Pathogenic, reviewed by expert panelcurationClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGenFeb 20, 2024NM_000329.3(RPE65):c.1338G>T is a missense variant that substitutes arginine with serine at position 446. The variant is found in multiple probands affected with early-onset severe retinal dystrophy. At least one patient genotyped by whole exome sequencing (2 pts) has a diagnosis of Leber congenital amaurosis (0.5 pts) with infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), and flat rod (0.5 pts) and cone (1 pt) ERG responses, which together are highly specific for RPE65-related recessive retinopathy (9.5 pts, PMID: 30870047, PP4_Moderate). At least 3 reported probands harbor the variant in the homozygous state, while an additional proband harbors this maternal variant in compound heterozygosity with a paternal c.361dup (p.Ser121Phefs*10 variant (previously classified pathogenic by the ClinGen LCA/eoRD VCEP)(PMID: 30870047, PM3_Strong). Three pairs of siblings have been reported (PMID: 30870047) harboring the variant in either the homozygous or compound heterozygous state (PP1). This variant has a Grpmax Filtering AF of 0.000009610 (2/34488, with no homozygotes) in the Latino/Admixed American population in gnomAD v2.1.1 which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002. Although the meta-predictor REVEL gives a score of 0.571, which is below the ClinGen LCA/eoRD VCEP PP3 threshold of >0.7, the computational splicing predictor SpliceAI indicates that the variant triggers the loss of a splice donor site, with a change score of 0.45. The variant was confirmed to exhibit a complete splicing defect in two minigene assays relative to the wild-type control, showing skipping of the 95-bp exon 12, indicating that it triggers nonsense-mediated decay (PMID: 30996589, PMID: 28714225, PVS1). 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: PVS1, PM2_Supporting, PM3_Strong, PP1, PP4_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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 08, 2022This variant is present in population databases (no rsID available, gnomAD 0.009%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 427864). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 26047050, 28714225, 30870047). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 446 of the RPE65 protein (p.Arg446Ser). This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
25
DANN
Benign
0.90
DEOGEN2
Uncertain
0.57
D
Eigen
Benign
-0.019
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.90
D
M_CAP
Uncertain
0.15
D
MetaRNN
Uncertain
0.71
D
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Benign
0.23
N
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
1.1
N
REVEL
Uncertain
0.57
Sift
Benign
0.81
T
Sift4G
Benign
0.99
T
Polyphen
0.0010
B
Vest4
0.92
MutPred
0.53
Gain of sheet (P = 0.1539);
MVP
0.97
MPC
0.061
ClinPred
0.31
T
GERP RS
5.1
Varity_R
0.43
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.45
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.45
Position offset: 0

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.

Other links and lift over

dbSNP: rs1420672586; hg19: chr1-68896965; API