1-197435404-T-C

Variant names:

• chr1-197435404-T-C
• rs62636291
• NM_201253.3:c.3541T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_201253.3(CRB1):​c.3541T>C​(p.Cys1181Arg) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1181S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 7.59
• Publications: 6 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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-197435404-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 987002.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, 0.989
• PP5: Variant 1-197435404-T-C is Pathogenic according to our data. Variant chr1-197435404-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 5737.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB1	NM_201253.3	c.3541T>C	p.Cys1181Arg	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	c.3541T>C	p.Cys1181Arg	missense_variant	Exon 9 of 12	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000297 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis Pathogenic:1

Jan 16, 2025

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa 12 Pathogenic:1

Jul 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinal dystrophy Pathogenic:1

Jan 01, 2017

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

Significance: Likely 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	0.90
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	T;.;D;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.5	D
MutationAssessor	Pathogenic	4.7	.;H;H;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-11	D;.;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0	D;.;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.96
MutPred		0.85		.;Gain of catalytic residue at C1181 (P = 0.0502);Gain of catalytic residue at C1181 (P = 0.0502);.;.;
MVP		0.99
MPC		0.29
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.99
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: rs62636291; hg19: chr1-197404534;