1-68438228-G-T

Variant names:

• chr1-68438228-G-T
• rs121917744
• NM_000329.3:c.1087C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PP1_Strong PP3 PS3_Supporting PP4_Moderate PM3

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant is reported in the literature in a homozygous state in at least two probands affected with Leber congenital amaurosis or early onset severe retinal dystrophy (1 point, PM3, PMID:9326941, PMID:26352687). At least one patient harboring the variant exhibited reduced or nondetectable rod ERG (required, 0.5 pts), decreased central visual acuity (1 pt), symptomatic onset between birth and age 5 years (1 pt), evidence of cone involvement on ERG (1 pt), light staring (1 pt), nyctalopia (0.5 pts), and positive response to RPE65 gene therapy (8 pts), which together are specific for RPE65-related recessive retinopathy (13 pts total, VCEP member-provided data, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy in multiple families with at least 3 members (PP1_strong, PMID:9326941, PMID:26352687). This variant is reported in ClinVar (Variation ID: 13117), and its Popmax Filtering AF in gnomAD v.2.1.1 is 0.00004443 (4/30608 alleles) in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP threshold (<0.0002) (PM2_Supporting). The meta-predictor REVEL gives a score of 0.702, which is above the ClinGen LCA/eoRD VCEP PP3 threshold of >0.644 and predicts a damaging effect on RPE65 function (PP3). An in vitro isomerohydrolase activity assay performed in adenovirus-infected 293A-LRAT cells showed that the p.Pro363Thr mutant exhibits complete loss of 11-cis-retinol production relative to the wild-type RPE65 control, confirming that this variant has a damaging effect on protein function (PMID:16828753, PS3_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: PP1_Strong, PM3, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA256730/MONDO:0100368/120

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: RPE65 NM_000329.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.48
• Publications: 13 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 11 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.1087C>A	p.Pro363Thr	missense	Exon 10 of 14	NP_000320.1	Q16518
	RPE65	NM_001406853.1		c.979C>A	p.Pro327Thr	missense	Exon 9 of 13	NP_001393782.1
	RPE65	NM_001406856.1		c.811C>A	p.Pro271Thr	missense	Exon 9 of 13	NP_001393785.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	ENST00000262340.6	TSL:1 MANE Select	c.1087C>A	p.Pro363Thr	missense	Exon 10 of 14	ENSP00000262340.5	Q16518
	RPE65	ENST00000713936.1		n.*992C>A		non_coding_transcript_exon	Exon 11 of 15	ENSP00000519233.1	A0AAQ5BH58
	RPE65	ENST00000713937.1		n.1087C>A		non_coding_transcript_exon	Exon 10 of 13	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251282 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461686 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111916

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Leber congenital amaurosis 2 (3)
2	-	-	Leber congenital amaurosis (2)
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	-	-	Retinitis pigmentosa 20 (1)
1	-	-	RPE65-related recessive retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.70
Sift	Benign	0.063	T
Sift4G	Benign	0.63	T
Polyphen		0.64	P
Vest4		0.96
MutPred		0.75		Gain of MoRF binding (P = 0.0359)
MVP		0.99
MPC		0.34
ClinPred		0.58	D
GERP RS		5.7
Varity_R		0.17
gMVP		0.86
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121917744; hg19: chr1-68903911;