rs786200886

Variant names:

• chr1-197477774-AAGGGCAACTC-A
• rs281865175
• NM_201253.3:c.4121_4130delCAACTCAGGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_201253.3(CRB1):​c.4121_4130delCAACTCAGGG​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. A1374A) has been classified as Likely benign.

• 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 18 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 23 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 rank	MANE	Protein	UniProt
CRB1	NM_201253.3	c.4121_4130delCAACTCAGGG	p.Ala1374GlufsTer20	frameshift_variant	Exon 12 of 12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.4121_4130delCAACTCAGGG	p.Ala1374GlufsTer20	frameshift_variant	Exon 12 of 12	1	NM_201253.3	ENSP00000356370.3

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

-

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 15, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 12 Pathogenic:2

Feb 15, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Other:1

May 27, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Leber congenital amaurosis Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Mar 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala1374Glufs*20) in the CRB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acid(s) of the CRB1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal 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. ClinVar contains an entry for this variant (Variation ID: 5740). This variant disrupts a region of the CRB1 protein in which other variant(s) (p.Arg1390*) have been determined to be pathogenic (PMID: 23379534, 29068479). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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;