NM_201253.3(CRB1):c.498_506del (p.Ile167_Gly169del) AND CRB1-related disorder

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 9, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004528300.1

Allele description [Variation Report for NM_201253.3(CRB1):c.498_506del (p.Ile167_Gly169del)]

NM_201253.3(CRB1):c.498_506del (p.Ile167_Gly169del)

Gene:

CRB1:crumbs cell polarity complex component 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

1q31.3

Genomic location:

Preferred name:

NM_201253.3(CRB1):c.498_506del (p.Ile167_Gly169del)

Other names:

NC_000001.10:g.197297979_197297987del; NP_957705.1:p.(Ile167_Gly169del)

HGVS:

NC_000001.11:g.197328849_197328857del
NG_008483.2:g.132388_132396del
NM_001193640.2:c.498_506del
NM_001257965.2:c.291_299del
NM_001257966.2:c.498_506del
NM_201253.3:c.498_506delMANE SELECT
NP_001180569.1:p.Ile167_Gly169del
NP_001244894.1:p.Ile98_Gly100del
NP_001244895.1:p.Ile167_Gly169del
NP_957705.1:p.Ile167_Gly169del
NC_000001.10:g.197297974_197297982del
NC_000001.10:g.197297974_197297982delGATGGAATT
NC_000001.10:g.197297974_197297982delGATGGAATT
NC_000001.10:g.197297979_197297987del
NC_000001.10:g.197297979_197297987delAATTGATGG
NM_001257965.1:c.291_299delAATTGATGG
NM_201253.2:c.498_506del
NM_201253.2:c.498_506del9
NM_201253.2:c.498_506delAATTGATGG
NR_047563.2:n.659_667del
NR_047564.2:n.659_667del

Links:

dbSNP: rs398124615

NCBI 1000 Genomes Browser:

rs398124615

Molecular consequence:

NM_001193640.2:c.498_506del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001257965.2:c.291_299del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001257966.2:c.498_506del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_201253.3:c.498_506del - inframe_deletion - [Sequence Ontology: SO:0001822]
NR_047563.2:n.659_667del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_047564.2:n.659_667del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: CRB1-related disorder
Synonyms:: CRB1-related condition; CRB1-Related Disorders
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000914374	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Aug 9, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25474345, 23379534, 27628848, 28041643, 27096895 Citation Link,
SCV004726875	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 9, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000914374

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Aug 9, 2018)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV004726875

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 9, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions.

Zaneveld J, Siddiqui S, Li H, Wang X, Wang H, Wang K, Li H, Ren H, Lopez I, Dorfman A, Khan A, Wang F, Salvo J, Gelowani V, Li Y, Sui R, Koenekoop R, Chen R.

Genet Med. 2015 Apr;17(4):262-70. doi: 10.1038/gim.2014.174. Epub 2014 Dec 4.

PubMed [citation]

PMID:: 25474345
PMCID:: PMC4385427

High frequency of CRB1 mutations as cause of Early-Onset Retinal Dystrophies in the Spanish population.

Corton M, Tatu SD, Avila-Fernandez A, Vallespín E, Tapias I, Cantalapiedra D, Blanco-Kelly F, Riveiro-Alvarez R, Bernal S, García-Sandoval B, Baiget M, Ayuso C.

Orphanet J Rare Dis. 2013 Feb 5;8:20. doi: 10.1186/1750-1172-8-20.

PubMed [citation]

PMID:: 23379534
PMCID:: PMC3637806

See all PubMed Citations (6)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000914374.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV004726875.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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