rs61752907

Variant names:

• chr1-68438962-C-A
• rs61752907
• NM_000329.3:c.978G>T

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 2 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.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.978G>T	p.Val326Val	synonymous	Exon 9 of 14	NP_000320.1
	RPE65	NM_001406853.1		c.870G>T	p.Val290Val	synonymous	Exon 8 of 13	NP_001393782.1
	RPE65	NM_001406856.1		c.702G>T	p.Val234Val	synonymous	Exon 8 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.978G>T	p.Val326Val	synonymous	Exon 9 of 14	ENSP00000262340.5
	RPE65	ENST00000713936.1		n.*883G>T		non_coding_transcript_exon	Exon 10 of 15	ENSP00000519233.1
	RPE65	ENST00000713937.1		n.978G>T		non_coding_transcript_exon	Exon 9 of 13	ENSP00000519234.1

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

GnomAD2 exomes AF: 0.000573 AC: 144 AN: 251402 AF XY: 0.000397

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 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

African (AFR) AF: 0.00502 AC: 168 AN: 33474

American (AMR) AF: 0.00116 AC: 52 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.000182 AC: 202 AN: 1111936

Other (OTH) AF: 0.00124 AC: 75 AN: 60392

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

African (AFR) AF: 0.00501 AC: 208 AN: 41490

American (AMR) AF: 0.00275 AC: 42 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67994

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.9
DANN	Benign	0.65
PhyloP100		-0.53
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs61752907; hg19: chr1-68904645;