NM_001904.4(CTNNB1):c.1420C>T (p.Arg474Ter) AND Severe intellectual disability-progressive spastic diplegia syndrome

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jan 7, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000677408.16

Allele description [Variation Report for NM_001904.4(CTNNB1):c.1420C>T (p.Arg474Ter)]

NM_001904.4(CTNNB1):c.1420C>T (p.Arg474Ter)

Genes:

LOC126806659:BRD4-independent group 4 enhancer GRCh37_chr3:41274918-41276117 [Gene]
CTNNB1:catenin beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.1

Genomic location:

Preferred name:

NM_001904.4(CTNNB1):c.1420C>T (p.Arg474Ter)

HGVS:

NC_000003.12:g.41233763C>T
NG_013302.2:g.39313C>T
NM_001098209.2:c.1420C>T
NM_001098210.2:c.1420C>T
NM_001330729.2:c.1399C>T
NM_001904.4:c.1420C>TMANE SELECT
NP_001091679.1:p.Arg474Ter
NP_001091680.1:p.Arg474Ter
NP_001317658.1:p.Arg467Ter
NP_001895.1:p.Arg474Ter
LRG_1108t1:c.1420C>T
LRG_1108:g.39313C>T
LRG_1108p1:p.Arg474Ter
NC_000003.11:g.41275254C>T
NM_001098210.1:c.1420C>T
NM_001904.3:c.1420C>T

Protein change:

R467*

Links:

dbSNP: rs1553631860

Molecular consequence:

NM_001098209.2:c.1420C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001098210.2:c.1420C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001330729.2:c.1399C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001904.4:c.1420C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Severe intellectual disability-progressive spastic diplegia syndrome (NEDSDV)
Synonyms:: NEURODEVELOPMENTAL DISORDER WITH SPASTIC DIPLEGIA AND VISUAL DEFECTS; CTNNB1 Neurodevelopmental Disorder
Identifiers:: MONDO: MONDO:0014035; MedGen: C3554449; Orphanet: 404473; OMIM: 615075

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000803712	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic (Mar 7, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001760123	Genomics England Pilot Project, Genomics England	no assertion criteria provided (ACGS Guidelines, 2016)	Pathogenic	germline	clinical testing	Citation Link,
SCV002059042	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 7, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25326669, 25741868
SCV002318925	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	no assertion criteria provided	Pathogenic	de novo	clinical testing
SCV002579785	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003807448	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.

Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, van den Boogaard MJ, Bramswig N, Büttner C, Cremer K, Czeschik JC, Engels H, van Gassen K, Graf E, van Haelst M, He W, Hogue JS, Kempers M, Koolen D, Monroe G, de Munnik S, Pastore M, et al.

Hum Genet. 2015 Jan;134(1):97-109. doi: 10.1007/s00439-014-1498-1. Epub 2014 Oct 19.

PubMed [citation]

PMID:: 25326669

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV000803712.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomics England Pilot Project, Genomics England, SCV001760123.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002059042.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000559636 /PMID: 25326669 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV002318925.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002579785.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807448.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PVS1 very strong, PS4 moderated, PM2 moderated, PM6 moderated

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jul 27, 2026

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