rs62635656

Positions:

chr1-197434985-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_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 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:10O:1

Conservation

PhyloP100: 5.88

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a domain Laminin G-like 3 (size 187) in uniprot entity CRUM1_HUMAN there are 52 pathogenic changes around while only 0 benign (100%) in NM_201253.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-197434984-A-G is described in Lovd as [Pathogenic].

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 id is 5730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197434985-T-C is described in Lovd as [Pathogenic]. Variant chr1-197434985-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB1	NM_201253.3 linkuse as main transcript	c.3122T>C	p.Met1041Thr	missense_variant	9/12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8 linkuse as main transcript	c.3122T>C	p.Met1041Thr	missense_variant	9/12	1	NM_201253.3	ENSP00000356370	P1	P82279-1

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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251068

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135678

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 8

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Retinitis pigmentosa 12

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2024	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. -

CRB1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 09, 2018

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;C3151202:Leber congenital amaurosis 8

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2023

For these reasons, this variant has been classified as Pathogenic. 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. 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. ClinVar contains an entry for this variant (Variation ID: 5730). 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. This variant is present in population databases (rs62635656, gnomAD 0.003%). 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). -

Pigmented paravenous retinochoroidal atrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided

Other:1

not provided, no classification provided

literature only

Retina International

- -

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

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;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over