rs137853136
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_201253.3(CRB1):c.3997G>A(p.Glu1333Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
CRB1
NM_201253.3 missense
NM_201253.3 missense
Scores
7
5
5
Clinical Significance
Conservation
PhyloP100: 6.13
Genes affected
CRB1 (HGNC:2343): (crumbs cell polarity complex component 1) This gene encodes a protein which is similar to the Drosophila crumbs protein and localizes to the inner segment of mammalian photoreceptors. In Drosophila crumbs localizes to the stalk of the fly photoreceptor and may be a component of the molecular scaffold that controls proper development of polarity in the eye. Mutations in this gene are associated with a severe form of retinitis pigmentosa, RP12, and with Leber congenital amaurosis. Alternate splicing results in multiple transcript variants, some protein coding and some non-protein coding.[provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_201253.3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.789
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRB1 | NM_201253.3 | c.3997G>A | p.Glu1333Lys | missense_variant | 11/12 | ENST00000367400.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRB1 | ENST00000367400.8 | c.3997G>A | p.Glu1333Lys | missense_variant | 11/12 | 1 | NM_201253.3 | P1 | |
ENST00000422250.1 | n.250C>T | non_coding_transcript_exon_variant | 2/4 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251414Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135874
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727240
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74346
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1333 of the CRB1 protein (p.Glu1333Lys). This variant is present in population databases (rs137853136, gnomAD 0.003%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 26667666; Invitae). ClinVar contains an entry for this variant (Variation ID: 632096). 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 CRB1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
CRB1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 04, 2017 | The CRB1 c.3997G>A (p.Glu1333Lys) missense variant has been reported in a single study in which i was reported in a compound heterozygous state with a second missense variant in one individual with autosomal recessive retinitis pigmentosa (Ge et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000027 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited evidence, the p.Glu1333Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for CRB1-related disorders. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 07, 2023 | Variant summary: CRB1 c.3997G>A (p.Glu1333Lys) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251414 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3997G>A has been reported in the literature in at least one compound heterozygous individual affected with Retinitis Pigmentosa (example: Ge_2015). These data do not allow any conclusion about variant significance. 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: 26667666). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=3) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Leber congenital amaurosis Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 15, 2020 | - - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 05, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;N
PrimateAI
Benign
T
PROVEAN
Benign
N;D;.;D;D;D
REVEL
Pathogenic
Sift
Benign
D;D;.;D;D;D
Sift4G
Uncertain
D;D;.;D;D;D
Polyphen
1.0
.;D;.;D;D;.
Vest4
MutPred
0.52
.;.;Gain of methylation at E1333 (P = 0.0103);Gain of methylation at E1333 (P = 0.0103);.;.;
MVP
MPC
0.24
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at