Frameshift 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: 25326669, 26845106, 28191889, 33004838, 33994118)
ClinVar Genomic variation as it relates to human health
NM_001904.4(CTNNB1):c.1925_1926del (p.Glu642fs)
Germline
Classification
Help
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.
(8)
Help
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.
Pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001904.4(CTNNB1):c.1925_1926del (p.Glu642fs)
Variation ID: 503703 Accession: VCV000503703.38
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 3p22.1 3: 41236468-41236469 (GRCh38) [ NCBI UCSC ] 3: 41277959-41277960 (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 Apr 2, 2018 Feb 14, 2024 Apr 27, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001904.4:c.1925_1926del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001895.1:p.Glu642fs frameshift NM_001904.4:c.1925_1926delAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001098209.2:c.1925_1926del NP_001091679.1:p.Glu642fs frameshift NM_001098210.2:c.1925_1926del NP_001091680.1:p.Glu642fs frameshift NM_001330729.2:c.1904_1905del NP_001317658.1:p.Glu635fs frameshift NM_001904.3:c.1925_1926del NC_000003.12:g.41236468AG[1] NC_000003.11:g.41277959AG[1] NG_013302.2:g.42018AG[1] LRG_1108:g.42018AG[1] LRG_1108t1:c.1925_1926del LRG_1108p1:p.Glu642fs - Protein change
- E642fs, E635fs
- Other names
- -
- Canonical SPDI
- NC_000003.12:41236467:AGAG:AG
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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
Help
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
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
401 | 779 | |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 22, 2022 | RCV000598918.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 31, 2017 | RCV000624274.9 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 27, 2023 | RCV001265236.10 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jul 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000709956.3
First in ClinVar: Apr 02, 2018 Last updated: Dec 03, 2022 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift 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: 25326669, 26845106, 28191889, 33004838, 33994118) (less)
|
|
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Pathogenic
(Jul 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742817.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian
|
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Pathogenic
(Oct 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450327.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV001468959.1
First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
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Pathogenic
(Jul 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Severe intellectual disability-progressive spastic diplegia syndrome
Affected status: unknown
Allele origin:
de novo
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001761163.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
Comment:
The de novo c.1925_1926del (p.Glu642ValfsTer5) variant identified in the CTNNB1 gene is the deletion of two nucleotides resulting in a frameshift of the protein at … (more)
The de novo c.1925_1926del (p.Glu642ValfsTer5) variant identified in the CTNNB1 gene is the deletion of two nucleotides resulting in a frameshift of the protein at amino acid 642/782 (exon 12/15), and is predicted to lead to the premature termination of the protein 5 amino acids downstream. This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. This variant is reported in ClinVar as Pathogenic (VarID:503703) and has been reported in multiple affected individuals in the literature [PMID:25326669,PMID:26845106]. Given its deleterious nature, presence de novo in this individual, absence in population databases, and observation in multiple affected individuals in the literature, the c.1925_1926del (p.Glu642ValfsTer5) variant identified in the CTNNB1 gene is reported as Pathogenic. (less)
Clinical Features:
Severe global developmental delay (present) , Intellectual disability (present) , Autistic behavior (present) , Lower limb spasticity (present) , Hypotonia (present) , Flexion contracture (present) … (more)
Severe global developmental delay (present) , Intellectual disability (present) , Autistic behavior (present) , Lower limb spasticity (present) , Hypotonia (present) , Flexion contracture (present) , Pes planus (present) , Strabismus (present) , High, narrow palate (present) (less)
Secondary finding: no
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Pathogenic
(Apr 27, 2023)
|
criteria provided, single submitter
Method: research
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Severe intellectual disability-progressive spastic diplegia syndrome
Affected status: yes
Allele origin:
germline
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Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)
Accession: SCV003920753.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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Pathogenic
(Aug 22, 2022)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001580867.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 503703). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 503703). This premature translational stop signal has been observed in individual(s) with microcephaly, developmental delay, intellectual disability, and severe hypotonia (PMID: 25326669, 26845106). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu642Valfs*5) 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). (less)
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Pathogenic
(Dec 10, 2018)
|
no assertion criteria provided
Method: provider interpretation
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Severe intellectual disability-progressive spastic diplegia syndrome
Affected status: yes
Allele origin:
de novo,
unknown
|
GenomeConnect - Simons Searchlight
Accession: SCV001443348.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-12-10 and interpreted as Pathogenic. The reporting laboratory … (more)
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-12-10 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. (less)
Observation 1:
Number of individuals with the variant: 1
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-11-22
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Sex: female
Testing laboratory: Ambry Genetics
Date variant was reported to submitter: 2017-08-25
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
The de novo c.1925_1926del (p.Glu642ValfsTer5) variant identified in the CTNNB1 gene is the deletion of two nucleotides resulting in a frameshift of the protein at amino acid 642/782 (exon 12/15), and is predicted to lead to the premature termination of the protein 5 amino acids downstream. This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. This variant is reported in ClinVar as Pathogenic (VarID:503703) and has been reported in multiple affected individuals in the literature [PMID:25326669,PMID:26845106]. Given its deleterious nature, presence de novo in this individual, absence in population databases, and observation in multiple affected individuals in the literature, the c.1925_1926del (p.Glu642ValfsTer5) variant identified in the CTNNB1 gene is reported as Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 503703). This premature translational stop signal has been observed in individual(s) with microcephaly, developmental delay, intellectual disability, and severe hypotonia (PMID: 25326669, 26845106). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu642Valfs*5) 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).
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-12-10 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
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. |
Comment:
Frameshift 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: 25326669, 26845106, 28191889, 33004838, 33994118)
Comment:
The de novo c.1925_1926del (p.Glu642ValfsTer5) variant identified in the CTNNB1 gene is the deletion of two nucleotides resulting in a frameshift of the protein at amino acid 642/782 (exon 12/15), and is predicted to lead to the premature termination of the protein 5 amino acids downstream. This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. This variant is reported in ClinVar as Pathogenic (VarID:503703) and has been reported in multiple affected individuals in the literature [PMID:25326669,PMID:26845106]. Given its deleterious nature, presence de novo in this individual, absence in population databases, and observation in multiple affected individuals in the literature, the c.1925_1926del (p.Glu642ValfsTer5) variant identified in the CTNNB1 gene is reported as Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 503703). This premature translational stop signal has been observed in individual(s) with microcephaly, developmental delay, intellectual disability, and severe hypotonia (PMID: 25326669, 26845106). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu642Valfs*5) 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).
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-12-10 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR. | Panagiotou ES | American journal of human genetics | 2017 | PMID: 28575650 |
| Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. | Monroe GR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26845106 |
| 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 rs1553632361 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.