NM_000329.3:c.1590C>A

Variant names:

• chr1-68429788-G-T
• NM_000329.3:c.1590C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3_Strong PP3_Moderate PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.1590C>A (p.Phe530Leu) variant is a missense variant in RPE65 causing a substitution of phenylalanine with leucine at position p.530. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.888, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the c.200T>G, p.L67R variant confirmed in trans (1 pt) or the c.118G>A p.Gly40Ser variant confirmed in trans (1 pt) (PMIDs: 36729443, 26047050), which were previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). This variant has also been reported in the compound heterozygous state with the p.Ala507Val and the c.335G>A p.Cys112Tyr, but were not counted for additional points to avoid circularity. At least one proband harboring this variant exhibits a phenotype including severely decreased rod ERG responses (0.5), symptomatic onset between birth and age five years (1), evidence of cone involvement on ERG (1), white/yellow dots on color photography in the context of severe retinal dysfunction (2), previous 100+ retinal dystrophy gene panel testing that did not provide an alternative explanation for visual impairment (2), which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID:33952291, 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, PP3_Moderate, PM3_Strong, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA340740550/MONDO:0100368/120

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RPE65 NM_000329.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 6.55

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.
• 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 rank	MANE	Protein	UniProt
RPE65	NM_000329.3	c.1590C>A	p.Phe530Leu	missense_variant	Exon 14 of 14	ENST00000262340.6	NP_000320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6	c.1590C>A	p.Phe530Leu	missense_variant	Exon 14 of 14	1	NM_000329.3	ENSP00000262340.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461352 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 530 of the RPE65 protein (p.Phe530Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Leber congenital amaurosis and/or retinitis pigmentosa (PMID: 25383945, 26047050, 33952291). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1470027). 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 80%. For these reasons, this variant has been classified as Pathogenic. -

Leber congenital amaurosis 2 Pathogenic:1

Mar 15, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.93	P
Vest4		0.87
MutPred		0.82		Loss of sheet (P = 0.0817);
MVP		1.0
MPC		0.20
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-68895471;