rs61751276

Variant names:

• chr1-68449890-C-T
• rs61751276
• NM_000329.3:c.11+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-68449890-C-T
• chr1-68449890-C-G

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3 PM2_Supporting PP3 PP1 PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.11+5G>A variant is a putative splicing variant in intron 1 of the RPE65 gene. The computational splicing predictor SpliceAI lists a change score of 0.58 for splice donor gain, predicting a deleterious impact on splicing (PP3). VCEP-member provided data from a mini-gene assay in HEK-293 cells show that this variant reduces normal splicing and leads to >400x reduction of mature mRNA, relative to the wild-type control (PS3_Supporting, Guan et al., 2024). At least 3 patients with this variant have been reported with detailed phenotypes (PMID:21211845, PMID:11786058), one of whom exhibited nonrecordable ERG responses from rods (0.5 pts) and cones (1 pt), congenital night blindness (0.5 pts), absence of autofluorescence (2 pts), optic nerve pallor (0.5 pts), RPE granularity (0.5 pts), onset between birth and age 5 years (1 pt), OCT preserved at macula (1 pt), constricted Goldmann visual field (1 pt), decreased central visual acuity (1 pt), and nystagmus (1 pt), which together are highly specific for recessive RPE65 retinopathy (10 pts total, VCEP member-provided data, PP4_Moderate). This variant has been detected in at least 7 published cases with recessive retinopathy, including at least two individuals homozygous for the variant (1 pt) and three individuals compound heterozygous for this variant in trans with either the c.615_616del (p.Ile206Cysfs*27), p.Glu102Ter, or c.89dup (p.Thr31fs) variant, all which have been classified Pathogenic by this VCEP (4pts, PMID:11095629, PMID:17525851, PMID:35129589), (PM3_Very-Strong). Two publications contain segregation data (PMID:11786058 and PMID:35001204), with one set of genotype-positive siblings exhibiting the required phenotype of absent or severely decreased rod electroretinogram response (PP1). The GrpMax Filtering AF for this variant in gnomAD v2.1.1 is 0.0001017 (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: PM3_Very-Strong, PP4_Moderate, PP1, PM2_Supporting, PP3, PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226483/MONDO:0100368/120

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: RPE65 NM_000329.3 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:25 O:1
• Conservation: PhyloP100: 5.18
• Publications: 24 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):

• retinitis pigmentosa

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Leber congenital amaurosis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• RPE65-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, ClinGen
• 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

Specifications for RPE65 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 8 ACMG points.

• PS3: 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.
• PP3: 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.11+5G>A		splice_region intron	N/A	NP_000320.1	Q16518
	RPE65	NM_001406853.1		c.11+5G>A		splice_region intron	N/A	NP_001393782.1
	RPE65	NM_001406856.1		c.-115+5G>A		splice_region 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.11+5G>A		splice_region intron	N/A	ENSP00000262340.5	Q16518
	RPE65	ENST00000713936.1		n.11+5G>A		splice_region intron	N/A	ENSP00000519233.1	A0AAQ5BH58
	RPE65	ENST00000713937.1		n.11+5G>A		splice_region intron	N/A	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000756 AC: 19 AN: 251324 AF XY: 0.0000736

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000158 AC: 231 AN: 1461760 Hom.: 0 Cov.: 30 AF XY: 0.000153 AC XY: 111 AN XY: 727194

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000201 AC: 224 AN: 1111908

Other (OTH) AF: 0.0000662 AC: 4 AN: 60392

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74372

African (AFR) AF: 0.0000965 AC: 4 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000147

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (8)
4	-	-	Leber congenital amaurosis 2 (4)
4	-	-	Retinitis pigmentosa 20 (4)
3	-	-	Retinal dystrophy (3)
2	-	-	Leber congenital amaurosis (2)
1	-	-	Inborn genetic diseases (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	-	-	RPE65-related disorder (1)
1	-	-	RPE65-related recessive retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.91
PhyloP100		5.2
PromoterAI		-0.38	Neutral
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61751276;

hg19: chr1-68915573;