rs34627040

Variant names:

• chr1-68431319-G-A
• rs34627040
• NM_000329.3:c.1301C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-68431319-G-A
• chr1-68431319-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2 BA1 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000329.3(RPE65):c.1301C>T (p.Ala434Val) missense variant that is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.07646, with 1976 alleles / 24962 total alleles in the African / African-American population with 72 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant has been reported in at least one patient with retinal dystrophy, however the phenotype is not specific to RPE65 and no second variant was described in trans (PMID:9501220). Three separate publications on families who carry this variant have reported unaffected individuals who harbor it in homozygous state (PMID:19431183, PMID:9501220, PMID:19920137, BS2). The computational predictor REVEL gives a score of 0.418, which is below the ClinGen LCA / eoRD VCEP threshold of ≥ 0.7 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.14, 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 110% or 55% enzymatic activity in two retinoid isomerase assays relative to the wild-type control, which are higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves normal protein function (PMID:19431183, 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, BS2, BS3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226501/MONDO:0100368/120

• Frequency:
  • Genomes: 𝑓 0.022 (109 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (113 hom.)
• Consequence: RPE65 NM_000329.3 missense
• Clinical Significance: Benign reviewed by expert panel B:12 O:1
• Conservation: PhyloP100: 7.38
• Publications: 12 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: Benign. The variant received -13 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.1301C>T	p.Ala434Val	missense	Exon 12 of 14	NP_000320.1	Q16518
	RPE65	NM_001406853.1		c.1193C>T	p.Ala398Val	missense	Exon 11 of 13	NP_001393782.1
	RPE65	NM_001406856.1		c.1025C>T	p.Ala342Val	missense	Exon 11 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.1301C>T	p.Ala434Val	missense	Exon 12 of 14	ENSP00000262340.5	Q16518
	RPE65	ENST00000713936.1		n.*1206C>T		non_coding_transcript_exon	Exon 13 of 15	ENSP00000519233.1	A0AAQ5BH58
	RPE65	ENST00000713937.1		n.*449C>T		non_coding_transcript_exon	Exon 11 of 13	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3353 AN: 152152 Hom.: 109 Cov.: 32

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00574 AC: 1441 AN: 250840 AF XY: 0.00412

Gnomad AFR exome AF: 0.0801

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00210 AC: 3065 AN: 1461654 Hom.: 113 Cov.: 32 AF XY: 0.00178 AC XY: 1293 AN XY: 727110

African (AFR) AF: 0.0771 AC: 2579 AN: 33462

American (AMR) AF: 0.00360 AC: 161 AN: 44688

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111886

Other (OTH) AF: 0.00431 AC: 260 AN: 60382

GnomAD4 genome AF: 0.0220 AC: 3349 AN: 152268 Hom.: 109 Cov.: 32 AF XY: 0.0205 AC XY: 1530 AN XY: 74460

African (AFR) AF: 0.0770 AC: 3200 AN: 41536

American (AMR) AF: 0.00693 AC: 106 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68032

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.00946 Hom.: 200

Bravo AF: 0.0240

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0751 AC: 331

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00697 AC: 846

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: 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	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	16
DANN	Benign	0.13
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0060	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.94	L
PhyloP100		7.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.92	N
REVEL	Uncertain	0.42
Sift	Benign	1.0	T
Sift4G	Benign	0.67	T
Polyphen		0.026	B
Vest4		0.54
MVP		0.96
MPC		0.056
ClinPred		0.041	T
GERP RS		5.1
Varity_R		0.14
gMVP		0.52
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs34627040; hg19: chr1-68897002;