rs61752907

Positions:

• chr1-68438962-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP7 BS1 BP4

This summary comes from the ClinGen Evidence Repository: The variant NM_000329.3(RPE65):c.978G>T, p.Val326= is a synonymous (silent) variant in exon 9. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.004399, with 376 alleles/74964 total alleles in the African/African American population, which is greater than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). 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: BS1, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226597/MONDO:0100368/120

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: RPE65 NM_000329.3 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:7 O:1
• Conservation: PhyloP100: -0.526

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

Verdict is Likely_benign. Variant got -6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPE65	NM_000329.3	c.978G>T	p.Val326=	synonymous_variant	9/14	ENST00000262340.6
LOC124904198	XR_007066164.1	n.72-9570C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPE65	ENST00000262340.6	c.978G>T	p.Val326=	synonymous_variant	9/14	1	NM_000329.3	P1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152004 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000573 AC: 144 AN: 251402 Hom.: 0 AF XY: 0.000397 AC XY: 54 AN XY: 135860

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000346 AC: 506 AN: 1461780 Hom.: 0 Cov.: 34 AF XY: 0.000323 AC XY: 235 AN XY: 727200

Gnomad4 AFR exome AF: 0.00502

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000182

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152122 Hom.: 1 Cov.: 32 AF XY: 0.00190 AC XY: 141 AN XY: 74356

Gnomad4 AFR AF: 0.00501

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000879 Hom.: 0

Bravo AF: 0.00193

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	RPE65: BP4, BP7 -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Leber congenital amaurosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 28, 2017

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 23, 2016

- -

RPE65-related recessive retinopathy Benign:1

Likely benign, reviewed by expert panel

curation

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

Apr 22, 2024

The variant NM_000329.3(RPE65):c.978G>T, p.Val326= is a synonymous (silent) variant in exon 9. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.004399, with 376 alleles/74964 total alleles in the African/African American population, which is greater than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). 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: BS1, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

Retinitis pigmentosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 28, 2017

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.9
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61752907; hg19: chr1-68904645;