NM_201253.3:c.1180T>C

Variant names:

• chr1-197421008-T-C
• rs786205450
• NM_201253.3:c.1180T>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_201253.3(CRB1):​c.1180T>C​(p.Cys394Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C394F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.48
• Publications: 7 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-197421009-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2106148.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, 0.958
• PP5: Variant 1-197421008-T-C is Pathogenic according to our data. Variant chr1-197421008-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 190990.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	c.1180T>C	p.Cys394Arg	missense_variant	Exon 6 of 12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.1180T>C	p.Cys394Arg	missense_variant	Exon 6 of 12	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive retinitis pigmentosa Pathogenic:1

Sep 10, 2015

Faculty of Health Sciences, Beirut Arab University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

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

Mar 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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 sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 394 of the CRB1 protein (p.Cys394Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 24265693). ClinVar contains an entry for this variant (Variation ID: 190990). -

Retinitis pigmentosa 12 Pathogenic:1

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;.;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.2	M;.;M;M;.
PhyloP100		7.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-11	D;D;.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;.;D;D
Polyphen		1.0, 1.0, 1.0	.;D;.;D;D
Vest4		0.97
MutPred		0.76		Gain of disorder (P = 0.0589);.;Gain of disorder (P = 0.0589);Gain of disorder (P = 0.0589);.;
MVP		0.98
MPC		0.29
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205450; hg19: chr1-197390138; COSMIC: COSV66332601; COSMIC: COSV66332601;