rs398124615

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PM1PM4PP5BS1_SupportingBS2

The NM_201253.3(CRB1):c.498_506delAATTGATGG(p.Ile167_Gly169del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00123 in 1,614,162 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 7 hom. )

Consequence

CRB1
NM_201253.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:20U:2B:1

Conservation

PhyloP100: 3.87

Publications

7 publications found

Variant links:

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]

CRB1 Gene-Disease associations (from GenCC):

hereditary macular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Leber congenital amaurosis 8
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
retinitis pigmentosa 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nanophthalmia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pigmented paravenous retinochoroidal atrophy
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_201253.3

PM4

Nonframeshift variant in NON repetitive region in NM_201253.3.

PP5

Variant 1-197328843-GGATGGAATT-G is Pathogenic according to our data. Variant chr1-197328843-GGATGGAATT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96659.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000775 (118/152348) while in subpopulation NFE AF = 0.00132 (90/68034). AF 95% confidence interval is 0.0011. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB1	NM_201253.3 link	c.498_506delAATTGATGG	p.Ile167_Gly169del	disruptive_inframe_deletion	Exon 2 of 12	ENST00000367400.8	NP_957705.1	P82279-1A0A7D6VM04

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8 link	c.498_506delAATTGATGG	p.Ile167_Gly169del	disruptive_inframe_deletion	Exon 2 of 12	1	NM_201253.3	ENSP00000356370.3		P82279-1

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000625

AC:

157

AN:

251256

AF XY:

0.000589

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000724

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000968

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00127

AC:

1863

AN:

1461814

Hom.:

AF XY:

0.00122

AC XY:

886

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33476

American (AMR)

AF:

0.000671

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00158

AC:

1754

AN:

1111968

Other (OTH)

AF:

0.000844

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

111

222

333

444

555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152348

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41592

American (AMR)

AF:

0.000915

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00132

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000249

Hom.:

Bravo

AF:

0.000903

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:20Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CRB1: PM3:Very Strong, PM2 -

Jan 27, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 28, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27628848, 25474345, 17297689, 30609409, 31047384, 32511120, 23379534, 27096895, 28041643, 27258436, 28819299, 28181551, 29391521, 29555955, 29869924, 31879567, 33773389, 33029571, 32037395) -

Macular dystrophy

Pathogenic:3

Sep 01, 2016

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 27, 2017

Molecular Medicine, University of Leeds

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

CRB1-related disorder

Pathogenic:2

Aug 09, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CRB1 c.498_506delAATTGATGG (p.Ile167_Gly169del) variant is an inframe deletion that has been reported in at least five studies in which it is identified in a total of 10 individuals, including in one in a homozygous state and in nine in a compound heterozygous state, and in three additional alleles (Corton et al. 2013; Zaneveld et al. 2015; Sergouniotis et al. 2016; Carss et al. 2017; Shah et al. 2017). Individuals with the variant present with a range of phenotypes including early-onset retinitis pigmentosa, Stargardt macular dystrophy, isolated maculopathy, macular dystrophy, and retinal dystrophy. No individuals with the variant have been reported with Leber congenital amaurosis or pigmented paravenous chorioretinal atrophy. Control data are unavailable for this variant, which is reported at a frequency of 0.00108 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the collective evidence, the p.Ile167_Gly169del variant is classified as pathogenic for CRB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CRB1 c.498_506del9 variant is predicted to result in an in-frame deletion (p.Ile167_Gly169del). This variant has been detected in the heterozygous, compound heterozygous, and homozygous states in patients with retinal disorders (Corton et al. 2013. PubMed ID: 23379534; Sergouniotis et al. 2016. PubMed ID: 27628848, Table S2; Zaneveld et al. 2015. PubMed ID: 25474345). This variant was found in all patients in a study of seven unrelated individuals who presented with macular dystrophy (Khan et al. 2018. PubMed ID: 29391521). The authors mentioned that this variant is the most prevalent disease-causing variant in non-Asian populations and may result in both mild and localized retinal dysfunction (Khan et al. 2018. PubMed ID: 29391521). This variant is reported with a global allele frequency of 0.062% in gnomAD including at least one homozygote, which is higher than expected for a fully-penetrant pathogenic variant. This variant is listed as pathogenic or likely pathogenic by the majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/96659/). At PreventionGenetics, we have observed this variant along with a protein truncating variant and in the absence of a second causative variant in several patients. Given the evidence, we interpret c.498_506del (p.Ile167_Gly169del) as likely pathogenic for autosomal recessive disease and uncertain for autosomal dominant disease. -

Leber congenital amaurosis 8

Pathogenic:2

Mar 30, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Retinal dystrophy

Pathogenic:2

Feb 15, 2018

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8

Pathogenic:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.498_506del, results in the deletion of 3 amino acid(s) of the CRB1 protein (p.Ile167_Gly169del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs748136623, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with retinal dystrophies (PMID: 23379534, 28181551; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 96659). For these reasons, this variant has been classified as Pathogenic. -

CRB1-related maculopathy

Pathogenic:1

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 12;C1868310:Pigmented paravenous retinochoroidal atrophy;C3151202:Leber congenital amaurosis 8

Pathogenic:1

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 1

Pathogenic:1

May 28, 2019

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive bestrophinopathy

Pathogenic:1

Nov 29, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ile98_Gly100del (NM_001257965.1 c.291_299delAATTGATGG) variant in CRB1 (al so reported as NM_201253.2:p.Ile167_Gly169del) has been previously reported in 1 homozygous and 7 compound heterozygous individuals with retinal disorders inclu ding retinal dystrophy, retinitis pigmentosa, and familial foveal retinoschisis (Corton 2013, Vincent 2016, Riera 2017). It has also been identified in 0.1% (12 4/126,500) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs748136623). This variant is a deletion of 3 amino acids at position 98-100, and it is unclear if this deletion will imp act the protein. In summary, although additional studies are required to fully e stablish its clinical significance, the p.Ile98_Gly100del variant is likely path ogenic for retinal disorders based on its biallelic occurrence individuals with these diseases. ACMG/AMP Criteria applied: PM3 (upgraded to Strong based on mult iple occurrences), PM4 (Richards 2015). -

Retinitis pigmentosa 12

Pathogenic:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa-12 (MIM#600105), Leber congenital amaurosis 8 (MIM#613835) and pigmented paravenous chorioretinal atrophy (MIM#172870). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). Pigmented paravenous chorioretinal atrophy is reported as autosomal dominant but with only a single variant as evidence (p.(Val162Met)) (PMID: 15623792). While it segregated within a large family, this variant has a high frequency in the population and poor conservation with recent papers questioning its pathogenicity (PMID: 30910914). (I) 0115 - Variants in this gene are known to have variable expressivity. Expression of retinal disease can be variable, even within families (PMIDs: 33387055; 29391521; 22065545). (I) 0216 - In-frame deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (172 heterozygotes, 1 homozygote). (SP) 0600 - Variant is located in the annotated calcium-binding EGF-like domain (NCBI Conserved domains). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in more than 20 patients with a range of retinal disease including early onset retinitis pigmentosa and macular dystrophy (ClinVar, PMIDs: 29391521; 33387055; 23379534). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cone dystrophy

Pathogenic:1

Jul 24, 2023

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Clinical significance based on ACMG v2.0 -

not specified

Benign:1

Sep 25, 2013

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.9

Mutation Taster

=99/101

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over