1-197477774-AAGGGCAACTC-A

Position:

• chr1-197477774-AAGGGCAACTC-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_201253.3(CRB1):​c.4121_4130del​(p.Ala1374GlufsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRB1 NM_201253.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.87

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-197477774-AAGGGCAACTC-A is Pathogenic according to our data. Variant chr1-197477774-AAGGGCAACTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 5740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197477774-AAGGGCAACTC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB1	NM_201253.3	c.4121_4130del	p.Ala1374GlufsTer20	frameshift_variant	12/12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.4121_4130del	p.Ala1374GlufsTer20	frameshift_variant	12/12	1	NM_201253.3	ENSP00000356370	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 8 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -

Retinitis pigmentosa 12 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2009	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 27, 2021	- -
not provided, no classification provided	literature only	Retina International	-	- -

Leber congenital amaurosis Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the CRB1 protein. Other variant(s) that disrupt this region (p.Arg1390*) have been determined to be pathogenic (PMID: 23379534, 29068479). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with inherited retinal dystrophy (PMID: 12567265). It has also been observed to segregate with disease in related individuals. This variant is also known as del 4121–4130 in the literature. ClinVar contains an entry for this variant (Variation ID: 5740). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CRB1 gene (p.Ala1374Glufs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acids of the CRB1 protein. -

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: rs281865175; hg19: chr1-197446904;