3-41234217-C-T

Variant names:

• chr3-41234217-C-T
• rs886039332
• NM_001904.4:c.1603C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001904.4(CTNNB1):​c.1603C>T​(p.Arg535*) variant causes a stop gained change involving the alteration of a non-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:13
• Conservation: PhyloP100: 1.49

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 3-41234217-C-T is Pathogenic according to our data. Variant chr3-41234217-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41234217-C-T is described in Lovd as [Pathogenic]. Variant chr3-41234217-C-T is described in Lovd as [Pathogenic]. Variant chr3-41234217-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.1603C>T	p.Arg535*	stop_gained	Exon 10 of 15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.1603C>T	p.Arg535*	stop_gained	Exon 10 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.1603C>T	p.Arg535*	stop_gained	Exon 10 of 16			ENSP00000494845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe intellectual disability-progressive spastic diplegia syndrome Pathogenic:7

Jan 09, 2025

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with spastic diplegia and visual defects (MIM#615075), and exudative vitreoretinopathy 7 (MIM#617572). However, somatic variants with a gain of function mechanism have been reported to cause cancer (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in two de novo individuals with intellectual disability (PMID: 27915094). It has also been reported multiple times as pathogenic in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 16, 2022

Laboratory of Human Genetics, Universidade de São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity. -

Feb 06, 2017

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-02-06 and interpreted as Pathogenic. Variant was initially reported on 2014-10-27 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -

Mar 18, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 09, 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: CTNNB1 c.1603C>T (p.Arg535X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251432 control chromosomes. c.1603C>T has been reported in the literature in individuals affected with Intellectual Disability (example: Kayumi_2022). The following publication has been ascertained in the context of this evaluation (PMID: 36083290). ClinVar contains an entry for this variant (Variation ID: 265085). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 05, 2018

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Feb 14, 2025

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: 36419413, 36943625, 33057194, 35982159, 25533962, 27915094, 31309540, 28135719, 30952489, 28191890, 26350204, 33425807, 31031587, 32334381, 31785789, 37009120, 36293418, 36083290) -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CTNNB1: PS2:Very Strong, PVS1, PM2, PS4:Moderate -

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg535*) in the CTNNB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTNNB1 are known to be pathogenic (PMID: 23033978, 24614104, 25326669, 26350204, 28575650). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CTNNB1-related conditions (PMID: 26350204, 27915094). ClinVar contains an entry for this variant (Variation ID: 265085). For these reasons, this variant has been classified as Pathogenic. -

Intellectual disability Pathogenic:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity Pathogenic:1

Oct 01, 2019

Stankiewicz Research Laboratory, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Exudative vitreoretinopathy 7 Pathogenic:1

May 18, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as de novo in at least two patients with syndromic developmental disorder [PMID 26350204, 27915094] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.95, 0.96, 0.95, 0.96
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Other links and lift over

dbSNP: rs886039332; hg19: chr3-41275708; COSMIC: COSV62715090; COSMIC: COSV62715090;