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

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Sep 19, 2023
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:: RCV000677408.14

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

NCBI 1000 Genomes Browser:

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
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 (Sep 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 35641310, 32555735, 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

Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL.

Cho BPH, Jolly AA, Nannoni S, Tozer D, Bell S, Markus HS.

Neurology. 2022 Aug 1;99(5):e430-e439. doi: 10.1212/WNL.0000000000200744.

PubMed [citation]

PMID:: 35641310
PMCID:: PMC9421602

Clinical and imaging features of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and cysteine-sparing NOTCH3 mutations.

Kim H, Lim YM, Lee EJ, Oh YJ, Kim KK.

PLoS One. 2020;15(6):e0234797. doi: 10.1371/journal.pone.0234797.

PubMed [citation]

PMID:: 32555735
PMCID:: PMC7302479

See all PubMed Citations (3)

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, SCV002059042.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.31 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NOTCH3 related disorder (PMID: 32555735).A different missense change at the same codon (p.Cys493Arg) has been reported to be associated with NOTCH3 related disorder (PMID: 35641310). Therefore, this variant is classified as Likely 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: Apr 20, 2025

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