rs1553263218

Positions:

• chr1-197435404-T-TG

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.3542dup​(p.Cys1181TrpfsTer13) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRB1 NM_201253.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.67

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-197435404-T-TG is Pathogenic according to our data. Variant chr1-197435404-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 438079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRB1	NM_201253.3	c.3542dup	p.Cys1181TrpfsTer13	frameshift_variant	9/12	ENST00000367400.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRB1	ENST00000367400.8	c.3542dup	p.Cys1181TrpfsTer13	frameshift_variant	9/12	1	NM_201253.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This sequence change creates a premature translational stop signal (p.Cys1181Trpfs*13) in the CRB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRB1 are known to be pathogenic (PMID: 10508521, 22065545, 23379534, 25412400, 26957898, 28041643, 29391521). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with inherited retinal dystrophy (PMID: 18055820, 28041643). This variant is also known as C1181InsG. ClinVar contains an entry for this variant (Variation ID: 438079). For these reasons, this variant has been classified as Pathogenic. -

Leber congenital amaurosis 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 07, 2023

- -

Retinal dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553263218; hg19: chr1-197404534;