NM_000474.4(TWIST1):c.419C>T (p.Ser140Leu) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 12, 2022
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:: RCV001943496.4

Allele description [Variation Report for NM_000474.4(TWIST1):c.419C>T (p.Ser140Leu)]

NM_000474.4(TWIST1):c.419C>T (p.Ser140Leu)

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.419C>T (p.Ser140Leu)

HGVS:

NC_000007.14:g.19116903G>A
NG_008114.2:g.5770C>T
NM_000474.3:c.419C>T
NM_000474.4:c.419C>TMANE SELECT
NP_000465.1:p.Ser140Leu
NC_000007.13:g.19156526G>A
NR_149001.2:n.734C>T

Protein change:

S140L

Links:

dbSNP: rs1554441987

NCBI 1000 Genomes Browser:

rs1554441987

Molecular consequence:

NM_000474.4:c.419C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_149001.2:n.734C>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

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SAMN14485788 (1)
SRA
abdominal-A, partial [Cataglyphis aenescens]
abdominal-A, partial [Cataglyphis aenescens]
gi|1632313845|gb|QCI61963.1|

Protein
abdominal-A, partial [Cataglyphis kurdistanica]
abdominal-A, partial [Cataglyphis kurdistanica]
gi|1632313827|gb|QCI61954.1|

Protein
abdominal-A, partial [Cataglyphis hispanica]
abdominal-A, partial [Cataglyphis hispanica]
gi|1632313817|gb|QCI61949.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002189547	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 12, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22544111, 33937142, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002189547

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 12, 2022)

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

Molecular genetic analysis of TWIST1 and FGFR3 genes in Korean patients with coronal synostosis: identification of three novel TWIST1 mutations.

Ko JM, Jeong SY, Yang JA, Park DH, Yoon SH.

Plast Reconstr Surg. 2012 May;129(5):814e-821e. doi: 10.1097/PRS.0b013e31824a2dda.

PubMed [citation]

PMID:: 22544111

Clinical and Genetic Characterization of Craniosynostosis in Saudi Arabia.

Alghamdi M, Alhumsi TR, Altweijri I, Alkhamis WH, Barasain O, Cardona-Londoño KJ, Ramakrishnan R, Guzmán-Vega FJ, Arold ST, Ali G, Adly N, Ali H, Basudan A, Bakhrebah MA.

Front Pediatr. 2021;9:582816. doi: 10.3389/fped.2021.582816.

PubMed [citation]

PMID:: 33937142
PMCID:: PMC8085561

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002189547.3

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

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.Ser140 amino acid residue in TWIST1. Other variant(s) that disrupt this residue have been observed in individuals with TWIST1-related conditions (PMID: 22544111), 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. This missense change has been observed in individuals with clinical features of Saethre-Chotzen syndrome (PMID: 33937142; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 140 of the TWIST1 protein (p.Ser140Leu).

#	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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