1-68431319-G-T

Position:

• chr1-68431319-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4 PP1 PP3 PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.1301C>A is a missense variant encoding a substitution of alanine by glutamic acid at codon 434. This variant is present in gnomAD v.4.0.0 at a frequency of 0.0000008994, with 1/1111886 alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In the Middle Eastern genetic ancestry group, the frequency of 1/5768 alleles (0.0001734) is also lower than the PM2_Supporting threshold. This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.1399C>G (p.Pro467Ala) variant confirmed in trans (1 pt, PMID:31273949), the NM_000329.3(RPE65):c.95-2A>T variant suspected in trans (0.5 pts, LOVD), or the NM_000329.3(RPE65):c.74C>T (p.Pro25Leu) variant suspected in trans (0.5 pts, PMID:29033008) all of which were previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID:31273949, PP1). The computational predictor REVEL gives a score of 0.769, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3). At least one proband harboring this variant exhibits a phenotype including extinguished rod ERG responses (0.5 pts), fundus albipunctatus / white dots (2 pts), onset between birth and age 5 years (1 pt), evidence of cone involvement on ERG (1 pt), and night blindness (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5 pts, PMID:31273949, PP4). 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 / eoRD VCEP: PM2_Supporting, PM3_Strong, PP1, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA340742486/MONDO:0100368/120

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPE65 NM_000329.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.38

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 Likely_pathogenic. Variant got 8 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.1301C>A	p.Ala434Glu	missense_variant	12/14	ENST00000262340.6	NP_000320.1
LOC124904198	XR_007066164.1	n.71+11198G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6	c.1301C>A	p.Ala434Glu	missense_variant	12/14	1	NM_000329.3	ENSP00000262340	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461660 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Apr 22, 2024

NM_000329.3(RPE65):c.1301C>A is a missense variant encoding a substitution of alanine by glutamic acid at codon 434. This variant is present in gnomAD v.4.0.0 at a frequency of 0.0000008994, with 1/1111886 alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In the Middle Eastern genetic ancestry group, the frequency of 1/5768 alleles (0.0001734) is also lower than the PM2_Supporting threshold. This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.1399C>G (p.Pro467Ala) variant confirmed in trans (1 pt, PMID: 31273949), the NM_000329.3(RPE65):c.95-2A>T variant suspected in trans (0.5 pts, LOVD), or the NM_000329.3(RPE65):c.74C>T (p.Pro25Leu) variant suspected in trans (0.5 pts, PMID: 29033008) all of which were previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 31273949, PP1). The computational predictor REVEL gives a score of 0.769, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3). At least one proband harboring this variant exhibits a phenotype including extinguished rod ERG responses (0.5 pts), fundus albipunctatus / white dots (2 pts), onset between birth and age 5 years (1 pt), evidence of cone involvement on ERG (1 pt), and night blindness (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5 pts, PMID: 31273949, PP4). 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 / eoRD VCEP: PM2_Supporting, PM3_Strong, PP1, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 850613). This missense change has been observed in individual(s) with early onset retinal disease (PMID: 31273949). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 434 of the RPE65 protein (p.Ala434Glu). -

Leber congenital amaurosis 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Laboratory of Genetics in Ophthalmology, Institut Imagine

-

- -

Leber congenital amaurosis Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.77
Sift	Benign	0.065	T
Sift4G	Benign	0.081	T
Polyphen		0.93	P
Vest4		0.89
MutPred		0.80		Gain of ubiquitination at K429 (P = 0.0542);
MVP		0.99
MPC		0.25
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.71
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs34627040; hg19: chr1-68897002;