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NM_001904.4(CTNNB1):c.807del (p.Met271fs) AND Severe intellectual disability-progressive spastic diplegia syndrome

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
May 2, 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:
RCV001195546.8

Allele description [Variation Report for NM_001904.4(CTNNB1):c.807del (p.Met271fs)]

NM_001904.4(CTNNB1):c.807del (p.Met271fs)

Gene:
CTNNB1:catenin beta 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
3p22.1
Genomic location:
Preferred name:
NM_001904.4(CTNNB1):c.807del (p.Met271fs)
Other names:
NM_001904.4(CTNNB1):c.807del; p.Met271fs
HGVS:
  • NC_000003.12:g.41225732del
  • NG_013302.2:g.31282del
  • NM_001098209.2:c.807del
  • NM_001098210.2:c.807del
  • NM_001330729.2:c.786del
  • NM_001904.4:c.807delMANE SELECT
  • NP_001091679.1:p.Met271fs
  • NP_001091680.1:p.Met271fs
  • NP_001317658.1:p.Met264fs
  • NP_001895.1:p.Met271fs
  • LRG_1108t1:c.807del
  • LRG_1108:g.31282del
  • LRG_1108p1:p.Met271fs
  • NC_000003.11:g.41267223del
  • NC_000003.11:g.41267223delT
Protein change:
M264fs
Links:
dbSNP: rs2078160286
NCBI 1000 Genomes Browser:
rs2078160286
Molecular consequence:
  • NM_001098209.2:c.807del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001098210.2:c.807del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001330729.2:c.786del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001904.4:c.807del - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
1

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001365931Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Pathogenic
(Dec 2, 2019) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003922193Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(May 2, 2023) 		germlinecuration

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown11not providednot providednot providedclinical testing, curation

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001365931.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The p.Met271TrpfsX5 variant in CTNNB1 has not been previously reported in individuals with neurodevelopmental disorder with spastic diplegia and visual defects and is absent from large population studies. However, this variant was confirmed to be de novo in an individual with global developmental delay with absent speech, autism spectrum disorder, hypotonia and hypertonia, dental abnormalities, and esotropia by the Broad Institute Rare Genomes Project. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 271 and is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the CTNNB1 gene is an established disease mechanism in individuals with neurodevelopmental disorder with spastic diplegia and visual defects. In summary, this variant meets criteria to be classified as pathogenic for neurodevelopmental disorder with spastic diplegia and visual defects in an autosomal dominant manner based upon de novo occurrence, its absence from the general population, and its predicted impact on the protein. ACMG/AMP Criteria applied: PS2, PM2, PVS1.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not provided1not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003922193.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The heterozygous p.Met271TrpfsTer5 variant in CTNNB1 was identified by our study in one individual with absent speech, autism spectrum disorder, developmental delay, hypotonia and hypertonia, dental anomalies, esotropia (Broad Institute Rare Genomes Project). Trio genome analysis showed this variant to be de novo. The p.Met271TrpfsTer5 variant in CTNNB1 has not been previously reported in the literature in individuals with neurodevelopmental disorder with spastic diplegia and visual defects. This variant has also been reported in ClinVar (Variation ID: 930112) and has been interpreted as pathogenic by Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 271 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the CTNNB1 gene is an established disease mechanism in autosomal dominant neurodevelopmental disorder with spastic diplegia and visual defects. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant neurodevelopmental disorder with spastic diplegia and visual defects. ACMG/AMP Criteria applied: PVS1, PS2_Supporting, PM2_Supporting (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 23, 2024