1-68439059-T-G

Variant names:

• chr1-68439059-T-G
• rs61752901
• NM_000329.3:c.881A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_Moderate BA1

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.881A>C is a missense variant that causes substitution of lysine with threonine at position 294. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.03554, with 1312 alleles / 35390 total alleles in the Admixed American population (with 33 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state (PMID:19431183) with the NM_000329.3(RPE65):c.1078G>C (p.Ala360Pro) variant in trans and a 22-bp deletion within exon 12 in cis (PMID:19431183). However, the proband was not counted for the PM3 or BP2 codes because the other two variants have not yet been classified by the ClinGen LCA / eoRD VCEP. The meta-predictor REVEL gives a score of 0.974, which is above the ClinGen LCA/eoRP VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 16%-68% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is between the ClinGen LCA / eoRD VCEP thresholds of <10% activity (PS3_Supporting) and >50% activity (BS3_Supporting), so neither functional study code is met (PMID:16150724, PMID:19431183). Another missense variant in the same codon, NM_000329.2; c.880A>G, (p.Lys294Glu), has been observed in a proband with early-onset severe retinal dystrophy (VCEP member-provided data), but has been classified as a variant of uncertain significance for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP, so the PM5_Supporting code is not met. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BA1 and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA146043/MONDO:0100368/120

• Frequency:
  • Genomes: 𝑓 0.0025 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (38 hom.)
• Consequence: RPE65 NM_000329.3 missense
• Clinical Significance: Likely benign reviewed by expert panel B:12 O:1
• Conservation: PhyloP100: 7.67
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• PP3: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	NM_000329.3	MANE Select	c.881A>C	p.Lys294Thr	missense	Exon 9 of 14	NP_000320.1
	RPE65	NM_001406853.1		c.773A>C	p.Lys258Thr	missense	Exon 8 of 13	NP_001393782.1
	RPE65	NM_001406856.1		c.605A>C	p.Lys202Thr	missense	Exon 8 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.881A>C	p.Lys294Thr	missense	Exon 9 of 14	ENSP00000262340.5
	RPE65	ENST00000713936.1		n.*786A>C		non_coding_transcript_exon	Exon 10 of 15	ENSP00000519233.1
	RPE65	ENST00000713937.1		n.881A>C		non_coding_transcript_exon	Exon 9 of 13	ENSP00000519234.1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 378 AN: 152170 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00527 AC: 1325 AN: 251234 AF XY: 0.00387

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0372

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00119 AC: 1737 AN: 1461810 Hom.: 38 Cov.: 34 AF XY: 0.00100 AC XY: 727 AN XY: 727198

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.0365 AC: 1634 AN: 44722

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

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111970

Other (OTH) AF: 0.00141 AC: 85 AN: 60392

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152288 Hom.: 7 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74454

African (AFR) AF: 0.000481 AC: 20 AN: 41550

American (AMR) AF: 0.0224 AC: 343 AN: 15290

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.000972 Hom.: 7

Bravo AF: 0.00569

ExAC AF: 0.00400 AC: 486

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 (2)
-	-	2	not provided (3)
-	-	1	Leber congenital amaurosis (1)
-	-	1	Leber congenital amaurosis 2 (1)
-	-	1	Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20;C5231465:Retinitis pigmentosa 87 with choroidal involvement (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	RPE65-related recessive retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0088	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.92
MVP		1.0
MPC		0.38
ClinPred		0.10	T
GERP RS		5.2
Varity_R		0.92
gMVP		0.96
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs61752901; hg19: chr1-68904742; COSMIC: COSV104574582;