rs1057518922

Variant names:

• chr1-68431281-C-T
• rs1057518922
• NM_000329.3:c.1338+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-68431281-C-T
• chr1-68431281-C-A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2_Supporting PM3_Supporting PP1 PP4 PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.1338+1G>A variant disrupts a canonical splice site in intron 12 and is predicted to lead to skipping of a critical exon, resulting in a frameshift, and likely nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant has been reported in 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1207_1210dup (p.Glu404AlafsTer4) variant confirmed in trans (0.5 points, PMID 32367544), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PM3_Supporting).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 (PP1; PMID:32367544). At least one proband harboring this variant was tested by exome sequencing (2.0) and exhibits a phenotype including optic disc pallor (0.5), pigmentary retinopathy with attenuated vessels (0.5), poor pupillary light response (0.5), RPE mottling (0.5), macular atrophy (0.5), and decreased peripheral (1.0) and central vision (1.0) which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID:32367544, PP4). This variant is present in gnomAD v.4.1.0 at an allele frequency of 8.478e-7 with 1/1179592 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002. 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, PP1, PP4, PM3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16043370/MONDO:0100368/120

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPE65 NM_000329.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 5.76
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Leber congenital amaurosis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• RPE65-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Ambry Genetics
• RPE65-related dominant retinopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen, PanelApp Australia
• retinitis pigmentosa 20

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa 87 with choroidal involvement

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

LOC124904198 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000329.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	NM_000329.3	MANE Select	c.1338+1G>A		splice_donor intron	N/A	NP_000320.1	Q16518
	RPE65	NM_001406853.1		c.1230+1G>A		splice_donor intron	N/A	NP_001393782.1
	RPE65	NM_001406856.1		c.1062+1G>A		splice_donor intron	N/A	NP_001393785.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	ENST00000262340.6	TSL:1 MANE Select	c.1338+1G>A		splice_donor intron	N/A	ENSP00000262340.5	Q16518
	RPE65	ENST00000713936.1		n.*1243+1G>A		splice_donor intron	N/A	ENSP00000519233.1	A0AAQ5BH58
	RPE65	ENST00000713937.1		n.*486+1G>A		splice_donor intron	N/A	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461238 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726966

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111552

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital blindness;C0035304:Retinal degeneration;C0476397:Abnormal electroretinogram;C4025846:Abnormality of vision (1)
1	-	-	Leber congenital amaurosis 2 (1)
1	-	-	Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 (1)
1	-	-	Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20;C5231465:Retinitis pigmentosa 87 with choroidal involvement (1)
1	-	-	Retinal dystrophy (1)
1	-	-	Retinitis pigmentosa 20 (1)
1	-	-	RPE65-related recessive retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		5.8
GERP RS		5.1
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.47		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057518922; hg19: chr1-68896964;