NM_000474.4(TWIST1):c.79dup (p.Gln27fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 9, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003804220.2

Allele description [Variation Report for NM_000474.4(TWIST1):c.79dup (p.Gln27fs)]

NM_000474.4(TWIST1):c.79dup (p.Gln27fs)

Gene:

TWIST1:twist family bHLH transcription factor 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

7p21.1

Genomic location:

Preferred name:

NM_000474.4(TWIST1):c.79dup (p.Gln27fs)

HGVS:

NC_000007.14:g.19117243dup
NG_008114.2:g.5430dup
NG_110536.1:g.418dup
NM_000474.4:c.79dupMANE SELECT
NP_000465.1:p.Gln27fs
NC_000007.13:g.19156865_19156866insG
NC_000007.13:g.19156866dup
NR_149001.2:n.394dup

Protein change:

Q27fs

Molecular consequence:

NM_000474.4:c.79dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_149001.2:n.394dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: TWIST1-related craniosynostosis (CRS1)
Synonyms:: Craniosynostosis 1
Identifiers:: MONDO: MONDO:0007399; MedGen: C4551902; Orphanet: 63440; OMIM: 123100

Name:: Saethre-Chotzen syndrome (SCS)
Synonyms:: ACS III; Acrocephalo-syndactyly, type 3; Chotzen syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007042; MedGen: C0175699; Orphanet: 794; OMIM: 101400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004595261	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10094188, 10749989, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004595261

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 9, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations within or upstream of the basic helix-loop-helix domain of the TWIST gene are specific to Saethre-Chotzen syndrome.

El Ghouzzi V, Lajeunie E, Le Merrer M, Cormier-Daire V, Renier D, Munnich A, Bonaventure J.

Eur J Hum Genet. 1999 Jan;7(1):27-33.

PubMed [citation]

PMID:: 10094188

Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location.

El Ghouzzi V, Legeai-Mallet L, Aresta S, Benoist C, Munnich A, de Gunzburg J, Bonaventure J.

Hum Mol Genet. 2000 Mar 22;9(5):813-9.

PubMed [citation]

PMID:: 10749989

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004595261.1

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TWIST1 protein in which other variant(s) (p.Leu159Phe) have been determined to be pathogenic (PMID: 10094188, 10749989; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with TWIST1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the TWIST1 gene (p.Gln27Profs*211). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 176 amino acid(s) of the TWIST1 protein and extend the protein by 34 additional amino acid residues.

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

Last Updated: Sep 29, 2024

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