NM_000474.4(TWIST1):c.443C>T (p.Thr148Ile) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 25, 2019
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:: RCV001212895.8

Allele description [Variation Report for NM_000474.4(TWIST1):c.443C>T (p.Thr148Ile)]

NM_000474.4(TWIST1):c.443C>T (p.Thr148Ile)

Genes:

LOC129998021:ATAC-STARR-seq lymphoblastoid active region 25682 [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.443C>T (p.Thr148Ile)

HGVS:

NC_000007.14:g.19116879G>A
NG_008114.2:g.5794C>T
NM_000474.4:c.443C>TMANE SELECT
NP_000465.1:p.Thr148Ile
NC_000007.13:g.19156502G>A
NM_000474.3:c.443C>T
NR_149001.2:n.758C>T

Protein change:

T148I

Links:

dbSNP: rs1788580077

NCBI 1000 Genomes Browser:

rs1788580077

Molecular consequence:

NM_000474.4:c.443C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_149001.2:n.758C>T - 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

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
SCV001384497	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 25, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9585583, 10649491, 16251895, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001384497

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 25, 2019)

germline

clinical testing

PubMed (4)
[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

Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations.

Paznekas WA, Cunningham ML, Howard TD, Korf BR, Lipson MH, Grix AW, Feingold M, Goldberg R, Borochowitz Z, Aleck K, Mulliken J, Yin M, Jabs EW.

Am J Hum Genet. 1998 Jun;62(6):1370-80.

PubMed [citation]

PMID:: 9585583
PMCID:: PMC1377134

Mutations in the human TWIST gene.

Gripp KW, Zackai EH, Stolle CA.

Hum Mutat. 2000;15(2):150-5. Review. Erratum in: Hum Mutat 2000;15(5):479.

PubMed [citation]

PMID:: 10649491

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001384497.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr148 amino acid residue in TWIST1. Other variant(s) that disrupt this residue have been observed in individuals with TWIST1-related conditions (PMID: 9585583, 10649491, 16251895), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individuals affected with clinical features of Saethre-Chotzen syndrome (PMID: 16251895, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 148 of the TWIST1 protein (p.Thr148Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine.

#	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

ClinVar

Relating variation to medicine