1-197435539-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_201253.3(CRB1):c.3676G>T(p.Gly1226*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CRB1
NM_201253.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.49

Publications

4 publications found

Variant links:

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]

CRB1 Gene-Disease associations (from GenCC):

hereditary macular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Leber congenital amaurosis 8
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
retinitis pigmentosa 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nanophthalmia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pigmented paravenous retinochoroidal atrophy
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 1-197435539-G-T is Pathogenic according to our data. Variant chr1-197435539-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 438080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB1	NM_201253.3 link	c.3676G>T	p.Gly1226*	stop_gained	Exon 9 of 12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8 link	c.3676G>T	p.Gly1226*	stop_gained	Exon 9 of 12	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000200

AC:

AN:

250214

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461146

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111672

Other (OTH)

AF:

0.0000166

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000304

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 8

Pathogenic:3

Mar 04, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant is predicted to cause nonsense-mediated decay in a gene where LOF is a known cause of pathogenicity (PVS1). Variant is not found in gnomAD genomes and homozygous allele count in gnomAD exomes is less than 0 (PM2). Prevalence in affected patients is greater compared to the general populace (PS4).

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinitis pigmentosa 12

Pathogenic:2

Mar 14, 2022

Pangenia Genomics, Pangenia Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The CRB1, c.3676G>T (p.Gly1226*) variant is a nonsense variant, creating a premature translational stop codon in the CRB1 gene. Loss of function variants in CRB1 are known to be pathogenic [PMID: 10508521, 22065545, 23379534, 26957898, 29391521]. This variant is detected in trans with a likely-pathogenic variant [CRB1, c.3017C>A (p.Ser1006Tyr)]. This variant is at extremely low frequency in population database. This variant has been observed in individuals affected with inherited retinal dystrophies [PMID: 21602930, 25356976, 28041643]. There are multiple submissions of this variant in ClinVar (Variation ID: 438080), all rated as Pathogenic.

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CRB1-related disorder

Pathogenic:1

Mar 14, 2025

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leber congenital amaurosis

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8

Pathogenic:1

Feb 02, 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.Gly1226*) 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 present in population databases (rs757740068, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with inherited retinal dystrophies (PMID: 21602930, 24938718, 25356976). ClinVar contains an entry for this variant (Variation ID: 438080). For these reasons, this variant has been classified as Pathogenic.

Pigmented paravenous retinochoroidal atrophy

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinitis pigmentosa

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.;.;.;.

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.0

.;.;.;.;.

MetaRNN

Benign

0.0

.;.;.;.;.

MutationAssessor

Benign

0.0

.;.;.;.;.

PhyloP100

9.5

PROVEAN

Benign

0.0

.;.;.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;.;.

Vest4

0.84

GERP RS

5.5

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over