1-68439294-A-G

Position:

• chr1-68439294-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_Supporting PM3 PP3_Moderate PP1 PP4

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.755T>C (p.Phe252Ser) is a missense variant in exon 8 of 14, changing the phenylalanine at position 252 to serine. The variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.986, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who is compound heterozygous with the NM_000329.3(RPE65):c.1360del (p.Thr454LeufsTer?) variant confirmed in trans (1 point, PMIDs:28130426), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3). NM_000329.3(RPE65):c.755T>C (p.Phe252Ser) has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID:28130426). At least one proband (RF.T.111, patient II-I) harboring this variant exhibits a phenotype including severely decreased ERG responses (0.5 pt), optic disc pallor (0.5pt), pigmentary retinopathy with attenuated vessels (0.5 pt), symptomatic onset between birth an age five years (1 pt), decreased peripheral vision (1 pt), abnormal color vision (1 pt), decreased central visual acuity (1 pt), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID:28130426, PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3, PP1, PP3_moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA340745829/MONDO:0100368/120

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RPE65 NM_000329.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 8.95

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_pathogenic. Variant got 7 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPE65	NM_000329.3	c.755T>C	p.Phe252Ser	missense_variant	8/14	ENST00000262340.6
LOC124904198	XR_007066164.1	n.72-9238A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPE65	ENST00000262340.6	c.755T>C	p.Phe252Ser	missense_variant	8/14	1	NM_000329.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461638 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPE65 protein function. ClinVar contains an entry for this variant (Variation ID: 556104). This missense change has been observed in individual(s) with rod-cone dystrophy (PMID: 28130426). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 252 of the RPE65 protein (p.Phe252Ser). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 12, 2018	- -

RPE65-related recessive retinopathy Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Apr 22, 2024

NM_000329.3(RPE65):c.755T>C (p.Phe252Ser) is a missense variant in exon 8 of 14, changing the phenylalanine at position 252 to serine. The variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.986, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who is compound heterozygous with the NM_000329.3(RPE65):c.1360del (p.Thr454LeufsTer?) variant confirmed in trans (1 point, PMIDs:28130426), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3). NM_000329.3(RPE65):c.755T>C (p.Phe252Ser) has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 28130426). At least one proband (RF.T.111, patient II-I) harboring this variant exhibits a phenotype including severely decreased ERG responses (0.5 pt), optic disc pallor (0.5pt), pigmentary retinopathy with attenuated vessels (0.5 pt), symptomatic onset between birth an age five years (1 pt), decreased peripheral vision (1 pt), abnormal color vision (1 pt), decreased central visual acuity (1 pt), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID: 28130426, PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3, PP1, PP3_moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 01, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28130426) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 09, 2024

Variant summary: RPE65 c.755T>C (p.Phe252Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250684 control chromosomes (gnomAD). c.755T>C has been reported in the literature in 2 siblings who were affected with retinal degeneration and were compound heterozygous with a pathogenic variant (Biswas_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28130426). ClinVar contains an entry for this variant (Variation ID: 556104). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.77		Gain of sheet (P = 0.1208);
MVP		1.0
MPC		0.45
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553153135; hg19: chr1-68904977;