chr1-197434985-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP2PP3PP5_Very_Strong

The NM_201253.3(CRB1):c.3122T>C(p.Met1041Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,614,008 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1041V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CRB1
NM_201253.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 5.88

Publications

22 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 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_201253.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-197434984-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 636016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.749

PP5

Variant 1-197434985-T-C is Pathogenic according to our data. Variant chr1-197434985-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 5730.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.3122T>C	p.Met1041Thr	missense_variant	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.3122T>C	p.Met1041Thr	missense_variant	Exon 9 of 12	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152214

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251068

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111878

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000131

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41586

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000148

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 20, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:3

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2017

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CRB1 c.3122T>C (p.Met1041Thr) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251068 control chromosomes. c.3122T>C has been reported in the literature in multiple individuals affected with Retinal Dystrophy (Mathijssen_2017, DenHollander_1999). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10508521, 27380427). ClinVar contains an entry for this variant (Variation ID: 5730). Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinitis pigmentosa 12

Pathogenic:2

Oct 01, 1999

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

- -

CRB1-related disorder

Pathogenic:1

Aug 09, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Across a selection of the available literature, the CRB1 c.3122T>C (p.Met1041Thr) missense variant has been reported in at least three studies in which it is found in a homozygous state in total of 37 individuals from two large families, the majority of whom were described as being affected with autosomal recessive retinitis pigmentosa (arRP) (den Hollander et al. 1999; Hettinga et al. 2016; Mathijssen et al. 2016). The p.Met1041Thr variant was also detected in a heterozygous state in six unaffected parents of affected individuals. An additional individual with arRP was reportedly heterozygous for the p.Met1041Thr but also carried likely causative variants in other genes associated with arRP (Eisenberger et al. 2013). To date, this variant has not been reported in association with autosomal dominant retinal disorders or other autosomal recessive phenotypes. The p.Met1041Thr variant was reported in a heterozygous state in 16 of 940 controls and is reported at a frequency of 0.000027 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Met1041Thr variant is classified as pathogenic for CRB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Pathogenic:1

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8

Pathogenic:1

Jul 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRB1 protein function. This variant disrupts the p.Met1041 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been observed in individuals with CRB1-related conditions (PMID: 10508521, 30543658), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5730). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1041 of the CRB1 protein (p.Met1041Thr). This variant is present in population databases (rs62635656, gnomAD 0.003%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 10508521, 27380427). It has also been observed to segregate with disease in related individuals. -

Pigmented paravenous retinochoroidal atrophy

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.50

D;.;D;.;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.66

T;.;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.75

D;D;D;D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Uncertain

2.3

.;M;M;.;.

PhyloP100

5.9

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.7

D;.;D;D;D

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;.;D;D;D

Sift4G

Benign

0.10

T;.;T;D;T

Polyphen

0.99

D;.;P;D;.

Vest4

0.84

MutPred

0.48

.;Gain of glycosylation at S1040 (P = 0.0205);Gain of glycosylation at S1040 (P = 0.0205);.;.;

MVP

0.91

MPC

0.037

ClinPred

0.79

GERP RS

5.7

Varity_R

0.78

gMVP

0.87

Mutation Taster

=4/96

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over