NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 15, 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:: RCV000244262.6

Allele description [Variation Report for NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu)]

NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu)

Gene:

TGFBR1:transforming growth factor beta receptor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q22.33

Genomic location:

Preferred name:

NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu)

HGVS:

NC_000009.12:g.99138006C>T
NG_007461.1:g.37877C>T
NM_001130916.3:c.491C>T
NM_001306210.2:c.734C>T
NM_004612.4:c.722C>TMANE SELECT
NP_001124388.1:p.Ser164Leu
NP_001293139.1:p.Ser245Leu
NP_004603.1:p.Ser241Leu
NC_000009.11:g.101900288C>T
NM_004612.2:c.722C>T
P36897:p.Ser241Leu

Protein change:

S164L; SER241LEU

Links:

UniProtKB: P36897#VAR_029482; OMIM: 190181.0005; dbSNP: rs111854391

NCBI 1000 Genomes Browser:

rs111854391

Molecular consequence:

NM_001130916.3:c.491C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306210.2:c.734C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004612.4:c.722C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

variation affecting protein function [Variation Ontology: 0003]

Condition(s)

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000548341	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 15, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 22414221, 16596670, 16791849, 18781618, 23884466, 25521989, 25944730, 28209770, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000548341

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 15, 2023)

germline

clinical testing

PubMed (9)
[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

TGFBR1 mutations associated with Loeys-Dietz syndrome are inactivating.

Cardoso S, Robertson SP, Daniel PB.

J Recept Signal Transduct Res. 2012 Jun;32(3):150-5. doi: 10.3109/10799893.2012.664553. Epub 2012 Mar 14.

PubMed [citation]

PMID:: 22414221

FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited.

Adès LC, Sullivan K, Biggin A, Haan EA, Brett M, Holman KJ, Dixon J, Robertson S, Holmes AD, Rogers J, Bennetts B.

Am J Med Genet A. 2006 May 15;140(10):1047-58.

PubMed [citation]

PMID:: 16596670

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000548341.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TGFBR1 function (PMID: 22414221). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFBR1 protein function. ClinVar contains an entry for this variant (Variation ID: 12524). This missense change has been observed in individual(s) with Loeys-Dietz syndrome and Furlong syndrome and aortic dissection and clinical features of Loeys-Dietz syndrome (PMID: 16596670, 16791849, 18781618, 23884466, 25521989, 25944730, 28209770). In at least one individual the variant was observed to be de novo. 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 241 of the TGFBR1 protein (p.Ser241Leu).

#	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: Mar 5, 2024

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