3-41225049-C-T

Variant names:

• chr3-41225049-C-T
• rs1553630279
• NM_001904.4:c.337C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001904.4(CTNNB1):​c.337C>T​(p.Gln113*) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

CTNNB1 (HGNC:2514): (catenin beta 1) The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

CTNNB1 Gene-Disease associations (from GenCC):

• exudative vitreoretinopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• severe intellectual disability-progressive spastic diplegia syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• exudative vitreoretinopathy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-41225049-C-T is Pathogenic according to our data. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41225049-C-T is described in CliVar as Pathogenic. Clinvar id is 451713.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
CTNNB1	NM_001904.4	c.337C>T	p.Gln113*	stop_gained	Exon 4 of 15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.337C>T	p.Gln113*	stop_gained	Exon 4 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.337C>T	p.Gln113*	stop_gained	Exon 4 of 16			ENSP00000494845.1
CTNNB1	ENST00000715152.1	n.337C>T		non_coding_transcript_exon_variant	Exon 4 of 16			ENSP00000520353.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jul 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27915094, 24668549, 33057194, 35982159) -

Severe intellectual disability-progressive spastic diplegia syndrome Pathogenic:1

Oct 05, 2017

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;provider interpretation

This variant was identified in a 15 year old female with severe intellectual disability, cerebral palsy and dysarthria that are all consistent with CTNNB1-related disorder. Specifically, her cerebral palsy is characterized by significant bilateral lower extremity hypertonus, primarily spastic but mixed quality that is consistent with this disorder. The c.337C>T variant was found to be de novo (PS2); maternity and paternity were confirmed.. The variant is absent from the ExAC and gnomAD databases (PM2). The variant is also an expected null variant in a gene where loss of function is a known mechanism of disease (PVS1). This variant was identified in a similary affected sibling suggesting potential germline mosaicism in a parent. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.9
Vest4		0.96
GERP RS		5.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1553630279; hg19: chr3-41266540;