ClinVar Genomic variation as it relates to human health
NM_001904.4(CTNNB1):c.1420C>T (p.Arg474Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001904.4(CTNNB1):c.1420C>T (p.Arg474Ter)
Variation ID: 559636 Accession: VCV000559636.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.1 3: 41233763 (GRCh38) [ NCBI UCSC ] 3: 41275254 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 27, 2018 Apr 15, 2024 Oct 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001904.4:c.1420C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001895.1:p.Arg474Ter nonsense NM_001098209.2:c.1420C>T NP_001091679.1:p.Arg474Ter nonsense NM_001098210.2:c.1420C>T NP_001091680.1:p.Arg474Ter nonsense NM_001330729.2:c.1399C>T NP_001317658.1:p.Arg467Ter nonsense NC_000003.12:g.41233763C>T NC_000003.11:g.41275254C>T NG_013302.2:g.39313C>T LRG_1108:g.39313C>T LRG_1108t1:c.1420C>T LRG_1108p1:p.Arg474Ter - Protein change
- R474*, R467*
- Other names
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- Canonical SPDI
- NC_000003.12:41233762:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CTNNB1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
384 | 748 | |
LOC126806659 | - | - | - | GRCh38 | - | 141 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Mar 17, 2022 | RCV000677408.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2023 | RCV001092247.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 10, 2020 | RCV001260750.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 24, 2021 | RCV001374918.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 28, 2022 | RCV002286777.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2022 | RCV003126902.3 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003883158.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
de novo
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Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV001437842.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
Method: targeted next-gen sequencing
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Pathogenic
(Feb 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV001572205.1
First in ClinVar: Apr 28, 2021 Last updated: Apr 28, 2021 |
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Severe intellectual disability-progressive spastic diplegia syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002059042.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000559636, PMID:25326669). Stop-gained (nonsense): … (more)
The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000559636, PMID:25326669). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Mild microcephaly (present) , Strabismus (present)
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Pathogenic
(Feb 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Microcephalic primordial dwarfism, Alazami type
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577572.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PVS1, PM2, PP3, PP5
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Pathogenic
(Dec 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Severe intellectual disability-progressive spastic diplegia syndrome
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579785.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Jan 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental disorder
Affected status: yes
Allele origin:
de novo
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Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV003803831.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Sex: male
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Pathogenic
(Oct 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001793852.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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: 28333917, 34758253, 27915094, 25326669, 27479843, 29786110, 31785789, 33004838) (less)
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Pathogenic
(Mar 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Severe intellectual disability-progressive spastic diplegia syndrome
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807448.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PVS1 very strong, PS4 moderated, PM2 moderated, PM6 moderated
Number of individuals with the variant: 1
Clinical Features:
Microcephaly (present) , Gait disturbance (present) , Obesity (present) , Delayed fine motor development (present) , Mild global developmental delay (present) , Cerebellar ataxia (present) … (more)
Microcephaly (present) , Gait disturbance (present) , Obesity (present) , Delayed fine motor development (present) , Mild global developmental delay (present) , Cerebellar ataxia (present) , Delayed speech and language development (present) , Aortic regurgitation (present) , Specific learning disability (present) , Global developmental delay (present) , Short stature (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(Oct 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001585620.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg474*) in the CTNNB1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg474*) 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 clinical features of CTNNB1-related conditions (PMID: 25326669, 27915094, 28333917). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 559636). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Exudative vitreoretinopathy 7
Severe intellectual disability-progressive spastic diplegia syndrome Neoplasm of ovary Medulloblastoma Pilomatrixoma Hepatocellular carcinoma Colorectal cancer
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
maternal
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Molecular Genetics Lab, CHRU Brest
Accession: SCV004697623.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
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Pathogenic
(Nov 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248662.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 07, 2018)
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no assertion criteria provided
Method: clinical testing
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Severe intellectual disability-progressive spastic diplegia syndrome
Affected status: yes
Allele origin:
de novo
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV000803712.1
First in ClinVar: Aug 27, 2018 Last updated: Aug 27, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Severe intellectual disability-progressive spastic diplegia syndrome
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760123.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Severe intellectual disability-progressive spastic diplegia syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002318925.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Sex: female
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR. | Panagiotou ES | American journal of human genetics | 2017 | PMID: 28575650 |
A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. | Vissers LELM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28333917 |
Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals. | Kharbanda M | European journal of medical genetics | 2017 | PMID: 27915094 |
Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability. | Grozeva D | Human mutation | 2015 | PMID: 26350204 |
De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. | Kuechler A | Human genetics | 2015 | PMID: 25326669 |
Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features. | Tucci V | The Journal of clinical investigation | 2014 | PMID: 24614104 |
Diagnostic exome sequencing in persons with severe intellectual disability. | de Ligt J | The New England journal of medicine | 2012 | PMID: 23033978 |
Text-mined citations for rs1553631860 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.