VCV000253000.35 - ClinVar

NM_001904.4(CTNNB1):c.268C>T (p.Arg90Ter)

Germline

Classification

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)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001904.4(CTNNB1):c.268C>T (p.Arg90Ter)

Variation ID: 253000 Accession: VCV000253000.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.1 3: 41224980 (GRCh38) [ NCBI UCSC ] 3: 41266471 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jul 9, 2016	Oct 20, 2024	Dec 6, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001904.4:c.268C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001895.1:p.Arg90Ter	nonsense
NM_001098209.2:c.268C>T	NP_001091679.1:p.Arg90Ter	nonsense
NM_001098210.2:c.268C>T	NP_001091680.1:p.Arg90Ter	nonsense
NM_001330729.2:c.247C>T	NP_001317658.1:p.Arg83Ter	nonsense
NC_000003.12:g.41224980C>T
NC_000003.11:g.41266471C>T
NG_013302.2:g.30530C>T
LRG_1108:g.30530C>T
LRG_1108t1:c.268C>T	LRG_1108p1:p.Arg90Ter

... more HGVS ... less HGVS

Protein change

R90*, R83*

Other names

Canonical SPDI

NC_000003.12:41224979:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10586151 dbSNP: rs1369821061 VarSome

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
Gene	OMIM	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.
CTNNB1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	399	777
LOC126806658	-	-	-	GRCh38	-	226

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.
Severe intellectual disability-progressive spastic diplegia syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 27, 2016	RCV000234865.2
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Dec 6, 2022	RCV000760810.32
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Sep 19, 2018	RCV001266683.3

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.
Pathogenic (Apr 27, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe intellectual disability-progressive spastic diplegia syndrome Affected status: yes Allele origin: de novo	Center of Genomic medicine, Geneva, University Hospital of Geneva Study: Final Reports_Cases2015_1 Accession: SCV000292242.1 First in ClinVar: Jul 09, 2016 Last updated: Jul 09, 2016	Comment: This variant in CTNNB1 was found in combination with an another variant in CAMTA1, in a patient with severe mental retardation, ataxia, microcephaly and epilepsy Age: 5-10 years Sex: male
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV001469000.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021
Pathogenic (Oct 13, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000890705.2 First in ClinVar: Mar 19, 2019 Last updated: Jul 24, 2021	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 in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge (less)
Pathogenic (Sep 19, 2018)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV001444860.2 First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023	Number of individuals with the variant: 1 Clinical Features: Motor delay (present) , Microcephaly (present) , Lower limb hypertonia (present) , Spastic diplegia (present) , Pointed chin (present) , Thin upper lip vermilion (present) … (more) Motor delay (present) , Microcephaly (present) , Lower limb hypertonia (present) , Spastic diplegia (present) , Pointed chin (present) , Thin upper lip vermilion (present) , Narrow forehead (present) , Neonatal hypoglycemia (present) , Leukopenia (present) , Hypothermia (present) , Brisk reflexes (present) , Growth delay (present) , Abnormality of lower lip (present) (less) Sex: male Ethnicity/Population group: Caucasian
Pathogenic (Dec 06, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003311708.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 28191889‚ 33004838‚ 23033978‚ 24614104‚ 25326669‚ 26350204‚ 28575650 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 253000). This premature translational stop signal has been observed in individual(s) with neurodevelopmental disorder (PMID: 28191889, 33004838). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg90*) 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)
Pathogenic (Oct 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001500317.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957910.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975299.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021

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 observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 253000). This premature translational stop signal has been observed in individual(s) with neurodevelopmental disorder (PMID: 28191889, 33004838). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg90*) 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).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.	Wang T	Nature communications	2020	PMID: 33004838
Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR.	Panagiotou ES	American journal of human genetics	2017	PMID: 28575650
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.	Stessman HA	Nature genetics	2017	PMID: 28191889
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 rs1369821061 ...

These 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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001904.4(CTNNB1):c.268C>T (p.Arg90Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1369821061 ...