1-197427454-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong

The NM_201253.3(CRB1):c.2129A>T(p.Glu710Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000539 in 1,613,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E710K) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

CRB1
NM_201253.3 missense, splice_region

Scores

Splicing: ADA: 0.002644

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.54

Publications

21 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 15 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_201253.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-197421956-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1469683.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 168 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -1.2832 (below the threshold of 3.09). Trascript score misZ: 0.62189 (below the threshold of 3.09). GenCC associations: The gene is linked to Leber congenital amaurosis 8, retinitis pigmentosa 12, pigmented paravenous retinochoroidal atrophy, hereditary macular dystrophy, retinitis pigmentosa, Leber congenital amaurosis, nanophthalmia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

PP5

Variant 1-197427454-A-T is Pathogenic according to our data. Variant chr1-197427454-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438073.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.2129A>T	p.Glu710Val	missense_variant, splice_region_variant	Exon 7 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.2129A>T	p.Glu710Val	missense_variant, splice_region_variant	Exon 7 of 12	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151592

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

250792

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461430

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000729

AC:

AN:

1111678

Other (OTH)

AF:

0.0000331

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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

AF:

0.0000264

AC:

AN:

151592

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73956

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41208

American (AMR)

AF:

0.00

AC:

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67952

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000198

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jun 29, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20591486, 32581362, 20956273, 28041643, 28559085)

Oct 05, 2019

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leber congenital amaurosis 8

Pathogenic:2

Mar 09, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinal dystrophy

Pathogenic:2

Aug 03, 2018

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Retinitis pigmentosa 12;C1868310:Pigmented paravenous retinochoroidal atrophy;C3151202:Leber congenital amaurosis 8

Pathogenic:1

Jan 15, 2024

Fulgent Genetics, Fulgent Genetics

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

Apr 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 710 of the CRB1 protein (p.Glu710Val). This variant is present in population databases (rs145282040, gnomAD 0.004%). This missense change has been observed in individual(s) with CRB1-related diseases (PMID: 20591486, 20956273, 28041643, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438073). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Glu710 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been observed in individuals with CRB1-related conditions (PMID: 15024725), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Retinitis pigmentosa 12

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pigmented paravenous retinochoroidal atrophy

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.;D;.;T

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

T;.;T;T;T

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

0.0

.;M;M;.;.

PhyloP100

5.5

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.2

D;.;D;D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0010

D;.;D;D;D

Sift4G

Uncertain

0.0020

D;.;D;D;D

Vest4

0.59

ClinPred

0.98

GERP RS

3.4

Varity_R

0.46

gMVP

0.79

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0026

dbscSNV1_RF

Benign

0.050

SpliceAI score (max)

0.16

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over