NM_001904.4(CTNNB1):c.1543C>T (p.Arg515Ter) AND Severe intellectual disability-progressive spastic diplegia syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Oct 2, 2021
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:: RCV000032859.36

Allele description [Variation Report for NM_001904.4(CTNNB1):c.1543C>T (p.Arg515Ter)]

NM_001904.4(CTNNB1):c.1543C>T (p.Arg515Ter)

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.1543C>T (p.Arg515Ter)

HGVS:

NC_000003.12:g.41234157C>T
NG_013302.2:g.39707C>T
NM_001098209.2:c.1543C>T
NM_001098210.2:c.1543C>T
NM_001330729.2:c.1522C>T
NM_001904.4:c.1543C>TMANE SELECT
NP_001091679.1:p.Arg515Ter
NP_001091680.1:p.Arg515Ter
NP_001317658.1:p.Arg508Ter
NP_001895.1:p.Arg515Ter
LRG_1108t1:c.1543C>T
LRG_1108:g.39707C>T
LRG_1108p1:p.Arg515Ter
NC_000003.11:g.41275648C>T
NM_001904.3:c.1543C>T

Protein change:

R508*; ARG515TER

Links:

OMIM: 116806.0018; dbSNP: rs397514554

NCBI 1000 Genomes Browser:

rs397514554

Molecular consequence:

NM_001098209.2:c.1543C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001098210.2:c.1543C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001330729.2:c.1522C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001904.4:c.1543C>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
SCV000056628	OMIM	no assertion criteria provided	Pathogenic (Nov 15, 2012)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000803690	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic (Sep 21, 2017)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002012010	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23033978, 25326669, 25741868
SCV002764660	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Feb 2, 2021)	de novo	clinical testing	Citation Link

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Summary from all submissions

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

Citations

PubMed

Diagnostic exome sequencing in persons with severe intellectual disability.

de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE.

N Engl J Med. 2012 Nov 15;367(20):1921-9. doi: 10.1056/NEJMoa1206524. Epub 2012 Oct 3.

PubMed [citation]

PMID:: 23033978

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

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000056628.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an individual with neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; 615075), de Ligt et al. (2012) identified a de novo heterozygous nonsense mutation in the CTNNB1 gene, arg515-to-ter (R515X).

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

From Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV000803690.1

#	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 3billion, SCV002012010.1

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

Description

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). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as de novoo in similary affected individuals (PMID:23033978, 25326669). 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	1	not provided	not provided		1	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV002764660.1

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

Last Updated: Oct 20, 2024

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