rs398124615

chr1-197328843-GGATGGAATT-Gchr1-197328843-GGATGGAATT-GGATGGAATTGATGGAATT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM4 PP5

The NM_201253.3(CRB1):c.498_506del(p.Ile167_Gly169del) variant causes a 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). Synonymous variant affecting the same amino acid position (i.e. D165D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (7 hom.)
• Consequence: CRB1 NM_201253.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17 U:2 B:1
• Conservation: PhyloP100: 3.87

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 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 id is 96659.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=9, Likely_benign=1, Likely_pathogenic=5}. Variant chr1-197328843-GGATGGAATT-G is described in Lovd as [Pathogenic]. Variant chr1-197328843-GGATGGAATT-G is described in Lovd as [Likely_pathogenic]. Variant chr1-197328843-GGATGGAATT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRB1	NM_201253.3	c.498_506del	p.Ile167_Gly169del	inframe_deletion	2/12	ENST00000367400.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRB1	ENST00000367400.8	c.498_506del	p.Ile167_Gly169del	inframe_deletion	2/12	1	NM_201253.3	P1

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152230 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000625 AC: 157 AN: 251256 Hom.: 1 AF XY: 0.000589 AC XY: 80 AN XY: 135808

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 SAS 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.: 7 AF XY: 0.00122 AC XY: 886 AN XY: 727196

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00158

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74504

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000249 Hom.: 1

Bravo AF: 0.000903

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:17 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	CRB1: PM3:Very Strong, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Macular dystrophy Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine, University of Leeds	Oct 27, 2017	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

CRB1-related disorder Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 09, 2024	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 has conflicting interpretations in ClinVar ranging from likely benign to pathogenic (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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 09, 2018	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. -

Leber congenital amaurosis 8 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -

Leber congenital amaurosis 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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; Invitae). 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. -

Autosomal recessive bestrophinopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 29, 2017

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). -

CRB1-related maculopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Molecular Genetics, University of Zurich

Jan 30, 2021

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 15, 2018

- -

Cone dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Jul 24, 2023

Clinical significance based on ACMG v2.0 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 25, 2013

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398124615; hg19: chr1-197297973;