chr1-68431319-G-A

Variant names:

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

Variant summary

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

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

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]

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPE65	NM_000329.3	c.1301C>T	p.Ala434Val	missense_variant	Exon 12 of 14	ENST00000262340.6	NP_000320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6	c.1301C>T	p.Ala434Val	missense_variant	Exon 12 of 14	1	NM_000329.3	ENSP00000262340.5

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

Gnomad4 AFR exome AF: 0.0771 AC: 2579 AN: 33462

Gnomad4 AMR exome AF: 0.00360 AC: 161 AN: 44688

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39692

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53390

Gnomad4 NFE exome AF: 0.0000432 AC: 48 AN: 1111886

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.0770 AC: 0.0770416 AN: 0.0770416

Gnomad4 AMR AF: 0.00693 AC: 0.00693264 AN: 0.00693264

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207039 AN: 0.000207039

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000220 AC: 0.000220484 AN: 0.000220484

Gnomad4 OTH AF: 0.0128 AC: 0.012772 AN: 0.012772

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

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Jun 14, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 16, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Benign:2

Mar 06, 2017

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RPE65-related recessive retinopathy Benign:1

Dec 22, 2023

ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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 greater than or equal to 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 greater than or equal to 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). -

Leber congenital amaurosis Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20;C5231465:Retinitis pigmentosa 87 with choroidal involvement Benign:1

Apr 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Retinitis pigmentosa Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs34627040; hg19: chr1-68897002;