rs61752901

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000329.3(RPE65):​c.881A>T​(p.Lys294Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K294T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

RPE65
NM_000329.3 missense

Scores

13
4
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.67
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-68439059-T-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPE65NM_000329.3 linkc.881A>T p.Lys294Ile missense_variant Exon 9 of 14 ENST00000262340.6 NP_000320.1 Q16518

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPE65ENST00000262340.6 linkc.881A>T p.Lys294Ile missense_variant Exon 9 of 14 1 NM_000329.3 ENSP00000262340.5 Q16518

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.97
D
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.76
T
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-6.5
D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.89
MutPred
0.74
Loss of disorder (P = 0.005);
MVP
1.0
MPC
0.45
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.91
gMVP
0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-68904742; API