NM_001904.4(CTNNB1):c.1603C>T (p.Arg535Ter) AND Severe intellectual disability-progressive spastic diplegia syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Mar 16, 2022
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:: RCV000495849.9

Allele description [Variation Report for NM_001904.4(CTNNB1):c.1603C>T (p.Arg535Ter)]

NM_001904.4(CTNNB1):c.1603C>T (p.Arg535Ter)

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.1603C>T (p.Arg535Ter)

HGVS:

NC_000003.12:g.41234217C>T
NG_013302.2:g.39767C>T
NM_001098209.2:c.1603C>T
NM_001098210.2:c.1603C>T
NM_001330729.2:c.1582C>T
NM_001904.4:c.1603C>TMANE SELECT
NP_001091679.1:p.Arg535Ter
NP_001091680.1:p.Arg535Ter
NP_001317658.1:p.Arg528Ter
NP_001895.1:p.Arg535Ter
LRG_1108t1:c.1603C>T
LRG_1108:g.39767C>T
LRG_1108p1:p.Arg535Ter
NC_000003.11:g.41275708C>T
NM_001904.3:c.1603C>T

Protein change:

R528*; ARG535TER

Links:

OMIM: 116806.0021; dbSNP: rs886039332

NCBI 1000 Genomes Browser:

rs886039332

Molecular consequence:

NM_001098209.2:c.1603C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001098210.2:c.1603C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001330729.2:c.1582C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001904.4:c.1603C>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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000583592	OMIM	no assertion criteria provided	Pathogenic (Mar 18, 2019)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000994578	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 5, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001443351	GenomeConnect - Simons Searchlight	no assertion criteria provided	Pathogenic (Feb 6, 2017)	de novo	provider interpretation
SCV002506519	Laboratory of Human Genetics, Universidade de São Paulo	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 16, 2022)	de novo	research	PubMed (1) [See all records that cite this PMID]

Help

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, research, provider interpretation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals.

Kharbanda M, Pilz DT, Tomkins S, Chandler K, Saggar A, Fryer A, McKay V, Louro P, Smith JC, Burn J, Kini U, De Burca A, FitzPatrick DR, Kinning E; DDD Study..

Eur J Med Genet. 2017 Feb;60(2):130-135. doi: 10.1016/j.ejmg.2016.11.008. Epub 2016 Nov 30.

PubMed [citation]

PMID:: 27915094
PMCID:: PMC6070129

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 OMIM, SCV000583592.6

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

Description

In 2 unrelated patients with neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; 615075), Kharbanda et al. (2017) identified heterozygosity for a de novo c.1603C-T transition in the CTNNB1 gene, resulting in an arg535-to-ter (R535X) substitution.

#	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 Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, SCV000994578.1

#	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 GenomeConnect - Simons Searchlight, SCV001443351.1

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

Description

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-02-06 and interpreted as Pathogenic. Variant was initially reported on 2014-10-27 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.

#	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 Laboratory of Human Genetics, Universidade de São Paulo, SCV002506519.1

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

Description

This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity.

#	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: Feb 20, 2024

ClinVar

Relating variation to medicine