chr1-68431282-C-A

Variant names:

• chr1-68431282-C-A
• rs1420672586
• NM_000329.3:c.1338G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2_Supporting PM3_Strong PP1 PP4_Moderate PVS1

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 ENST00000262340.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 5.67
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae)
• RPE65-related recessive retinopathy

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

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• 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 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262340.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	NM_000329.3	MANE Select	c.1338G>T	p.Arg446Ser	missense splice_region	Exon 12 of 14	NP_000320.1
	RPE65	NM_001406853.1		c.1230G>T	p.Arg410Ser	missense splice_region	Exon 11 of 13	NP_001393782.1
	RPE65	NM_001406856.1		c.1062G>T	p.Arg354Ser	missense splice_region	Exon 11 of 13	NP_001393785.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	ENST00000262340.6	TSL:1 MANE Select	c.1338G>T	p.Arg446Ser	missense splice_region	Exon 12 of 14	ENSP00000262340.5
	RPE65	ENST00000713936.1		n.*1243G>T		splice_region non_coding_transcript_exon	Exon 13 of 15	ENSP00000519233.1
	RPE65	ENST00000713937.1		n.*486G>T		splice_region non_coding_transcript_exon	Exon 11 of 13	ENSP00000519234.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152122 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250622 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.0000672 AC: 3 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111500

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.000262 AC: 4 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Leber congenital amaurosis (2)
1	-	-	Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 (1)
1	-	-	RPE65-related recessive retinopathy (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.7
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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1420672586; hg19: chr1-68896965;