3-41234217-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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
NM_001904.4 stop_gained
Scores
3
3
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CTNNB1 | NM_001904.4 | c.1603C>T | p.Arg535* | stop_gained | 10/15 | ENST00000349496.11 | NP_001895.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Severe intellectual disability-progressive spastic diplegia syndrome Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 09, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | Dec 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | research | Laboratory of Human Genetics, Universidade de São Paulo | Mar 16, 2022 | This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity. - |
| Pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Feb 06, 2017 | 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. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 18, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 16, 2023 | 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 - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 22, 2021 | 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25533962, 27915094, 31309540, 28135719, 30952489, 28191890, 26350204, 33425807, 31031587, 32334381, 31785789) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | CTNNB1: PS2:Very Strong, PVS1, PM2, PS4:Moderate - |
Intellectual disability Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Sep 10, 2020 | - - |
Abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | Stankiewicz Research Laboratory, Baylor College of Medicine | Oct 01, 2019 | - - |
Exudative vitreoretinopathy 7 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 18, 2018 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
0.95, 0.96, 0.95, 0.96
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at