rs61752878

Variant names:

• chr1-68444632-C-T
• rs61752878
• NM_000329.3:c.394G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS3_Supporting BA1

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.394G>A is a missense variant that replaces alanine with threonine at codon 132. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01113, with 372 alleles / 30614 total alleles in the South Asian population (with 6 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The computational predictor REVEL gives a score of 0.548, which is above the ClinGen LCA / eoRD VCEP threshold of <0.3 and does not strongly predict a non-damaging effect on RPE65 function. The splicing impact predictor SpliceAI gives a score of 0.03 for splice acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. The variant exhibited 50% enzymatic activity in an isomerohydrolase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves] normal protein function (PMID:16150724, BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226547/MONDO:0100368/120

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (26 hom.)
• Consequence: RPE65 NM_000329.3 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:11 O:1
• Conservation: PhyloP100: 5.74
• Publications: 23 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

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

Our verdict: Benign. The variant received -9 ACMG points.

• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.394G>A	p.Ala132Thr	missense	Exon 5 of 14	NP_000320.1	Q16518
	RPE65	NM_001406853.1		c.286G>A	p.Ala96Thr	missense	Exon 4 of 13	NP_001393782.1
	RPE65	NM_001406856.1		c.118G>A	p.Ala40Thr	missense	Exon 4 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.394G>A	p.Ala132Thr	missense	Exon 5 of 14	ENSP00000262340.5	Q16518
	RPE65	ENST00000713936.1		n.*299G>A		non_coding_transcript_exon	Exon 6 of 15	ENSP00000519233.1	A0AAQ5BH58
	RPE65	ENST00000713937.1		n.394G>A		non_coding_transcript_exon	Exon 5 of 13	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00294 AC: 739 AN: 251320 AF XY: 0.00352

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000836

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00168 AC: 2456 AN: 1461858 Hom.: 26 Cov.: 32 AF XY: 0.00200 AC XY: 1451 AN XY: 727232

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 543 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0116 AC: 999 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.000595 AC: 662 AN: 1111992

Other (OTH) AF: 0.00306 AC: 185 AN: 60394

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74446

African (AFR) AF: 0.0000963 AC: 4 AN: 41546

American (AMR) AF: 0.000719 AC: 11 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4818

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00168 Hom.: 3

Bravo AF: 0.00112

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00287 AC: 348

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Leber congenital amaurosis 2 (3)
-	-	2	Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 (2)
-	-	2	not provided (3)
-	1	-	Leber congenital amaurosis (1)
-	-	1	not specified (1)
-	-	1	Retinal dystrophy (1)
-	1	-	Retinitis pigmentosa 20 (1)
-	-	1	RPE65-related disorder (1)
-	-	1	RPE65-related recessive retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.0099
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.55
Sift	Benign	0.50	T
Sift4G	Benign	0.47	T
Polyphen		0.012	B
Vest4		0.78
MVP		0.96
MPC		0.054
ClinPred		0.019	T
GERP RS		5.0
Varity_R		0.23
gMVP		0.54
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61752878; hg19: chr1-68910315;