NM_000474.4(TWIST1):c.352C>A (p.Arg118Ser) AND Saethre-Chotzen syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 17, 2020
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:: RCV002466653.1

Allele description [Variation Report for NM_000474.4(TWIST1):c.352C>A (p.Arg118Ser)]

NM_000474.4(TWIST1):c.352C>A (p.Arg118Ser)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

7p21.1

Genomic location:

Preferred name:

NM_000474.4(TWIST1):c.352C>A (p.Arg118Ser)

HGVS:

NC_000007.14:g.19116970G>T
NG_008114.2:g.5703C>A
NM_000474.4:c.352C>AMANE SELECT
NP_000465.1:p.Arg118Ser
NC_000007.13:g.19156593G>T
NM_000474.3:c.352C>A
NR_149001.2:n.667C>A

Protein change:

R118S

Links:

dbSNP: rs1554442015

NCBI 1000 Genomes Browser:

rs1554442015

Molecular consequence:

NM_000474.4:c.352C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_149001.2:n.667C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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
SCV002761593	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 17, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9259286, 11854168, 16251895, 19952666, 23527594, 29304373, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002761593

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 17, 2020)

germline

clinical testing

PubMed (7)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The TWIST gene, although not disrupted in Saethre-Chotzen patients with apparently balanced translocations of 7p21, is mutated in familial and sporadic cases.

Rose CS, Patel P, Reardon W, Malcolm S, Winter RM.

Hum Mol Genet. 1997 Aug;6(8):1369-73.

PubMed [citation]

PMID:: 9259286

Twist haploinsufficiency in Saethre-Chotzen syndrome induces calvarial osteoblast apoptosis due to increased TNFalpha expression and caspase-2 activation.

Yousfi M, Lasmoles F, El Ghouzzi V, Marie PJ.

Hum Mol Genet. 2002 Feb 15;11(4):359-69.

PubMed [citation]

PMID:: 11854168

See all PubMed Citations (7)

Details of each submission

From Genetics and Molecular Pathology, SA Pathology, SCV002761593.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

PM1, PM2, PM5, PP1 The TWIST1 c.352C>A variant is a single nucleotide change from a cytosine to an adenine at position 352 which is predicted to alter the amino acid arginine at position 118 in the protein to serine. This variant in exon 1 is in the Helix-loop-helix-DNA-binding domain. The variant has not been reported in dbSNP and is absent from population databases (PM2). The Arg118Ser variant has been previously reported in a patient with Saethre-Chotzen syndrome (PMID:19952666) (PP1). Molecular dynamics simulations studies suggest that the Arg118 residue is critical for the formation of TWIST1-DNA complex structures (PMID: 23527594), but the functional effect of an Arg118Ser substitution was not investigated (PM1 applied as the residue is a critical part of the domain). The variant has not been reported in the ClinVar or LOVD disease databases, but there are multiple reports of other (likely) pathogenic missense variants at Arg118: Arg118Cys (PMID: 11854168); Arg118Gly (PMID: 29304373); Arg118His (PMID: 9259286); Arg118Pro (PMID: 16251895) (PM5). Computational predictions support a deleterious effect (PP3 not applied as PM5 applied already).

#	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

Last Updated: Jan 7, 2023

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