NM_003242.6(TGFBR2):c.1408T>G (p.Tyr470Asp) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 21, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002310796.10

Allele description [Variation Report for NM_003242.6(TGFBR2):c.1408T>G (p.Tyr470Asp)]

NM_003242.6(TGFBR2):c.1408T>G (p.Tyr470Asp)

Gene:

TGFBR2:transforming growth factor beta receptor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p24.1

Genomic location:

Preferred name:

NM_003242.6(TGFBR2):c.1408T>G (p.Tyr470Asp)

HGVS:

NC_000003.12:g.30688395T>G
NG_007490.1:g.86894T>G
NM_001024847.3:c.1483T>G
NM_001407126.1:c.1591T>G
NM_001407127.1:c.1516T>G
NM_001407128.1:c.1435T>G
NM_001407129.1:c.1411T>G
NM_001407130.1:c.1405T>G
NM_001407132.1:c.1303T>G
NM_001407133.1:c.1303T>G
NM_001407134.1:c.1303T>G
NM_001407135.1:c.1303T>G
NM_001407136.1:c.1303T>G
NM_001407137.1:c.1123T>G
NM_001407138.1:c.1048T>G
NM_001407139.1:c.538T>G
NM_003242.6:c.1408T>GMANE SELECT
NP_001020018.1:p.Tyr495Asp
NP_001020018.1:p.Tyr495Asp
NP_001394055.1:p.Tyr531Asp
NP_001394056.1:p.Tyr506Asp
NP_001394057.1:p.Tyr479Asp
NP_001394058.1:p.Tyr471Asp
NP_001394059.1:p.Tyr469Asp
NP_001394061.1:p.Tyr435Asp
NP_001394062.1:p.Tyr435Asp
NP_001394063.1:p.Tyr435Asp
NP_001394064.1:p.Tyr435Asp
NP_001394065.1:p.Tyr435Asp
NP_001394066.1:p.Tyr375Asp
NP_001394067.1:p.Tyr350Asp
NP_001394068.1:p.Tyr180Asp
NP_003233.4:p.Tyr470Asp
LRG_779t1:c.1483T>G
LRG_779t2:c.1408T>G
LRG_779:g.86894T>G
LRG_779p1:p.Tyr495Asp
LRG_779p2:p.Tyr470Asp
NC_000003.11:g.30729887T>G
NM_001024847.2:c.1483T>G
NM_003242.5:c.1408T>G

Protein change:

Y180D

Links:

dbSNP: rs863224935

NCBI 1000 Genomes Browser:

rs863224935

Molecular consequence:

NM_001024847.3:c.1483T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407126.1:c.1591T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407127.1:c.1516T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407128.1:c.1435T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407129.1:c.1411T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407130.1:c.1405T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407132.1:c.1303T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407133.1:c.1303T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407134.1:c.1303T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407135.1:c.1303T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407136.1:c.1303T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407137.1:c.1123T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407138.1:c.1048T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407139.1:c.538T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_003242.6:c.1408T>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000318668	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Feb 3, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17418587, 24983314, 25326637, 9927040 Citation Link,
SCV003482752	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 21, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26848186, 27879313, 25326637, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000318668

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Feb 3, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV003482752

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 21, 2022)

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	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Genetic testing in patients with aortic aneurysms/dissections: a novel genotype/phenotype correlation?

Waldmüller S, Müller M, Warnecke H, Rees W, Schöls W, Walterbusch G, Ennker J, Scheffold T.

Eur J Cardiothorac Surg. 2007 Jun;31(6):970-5. Epub 2007 Apr 5.

PubMed [citation]

PMID:: 17418587

Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling.

Chen X, Wang H, Liao HJ, Hu W, Gewin L, Mernaugh G, Zhang S, Zhang ZY, Vega-Montoto L, Vanacore RM, Fässler R, Zent R, Pozzi A.

J Clin Invest. 2014 Aug;124(8):3295-310. doi: 10.1172/JCI71668. Epub 2014 Jul 1.

PubMed [citation]

PMID:: 24983314
PMCID:: PMC4109532

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000318668.6

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

Description

The p.Y470D pathogenic mutation (also known as c.1408T>G), located in coding exon 6 of the TGFBR2 gene, results from a T to G substitution at nucleotide position 1408. The tyrosine at codon 470 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant has been previously reported in an individual with suspected Marfan or Loeys-Dietz syndrome (Lee H et al. JAMA 2014 Nov; 312(18):1880-7) and segregates with disease in one family tested in our laboratory (Ambry internal data). In a study of patients with aortic aneurysms/dissections, an alteration of the same codon, p.Y470S (c.1409A>C), in the protein kinase domain was detected in one patient (Waldmüller S et al. Eur J Cardiothorac Surg. 2007;31(6):970-5). Phosphorylation of p.Y470 has been shown to be important for TGFBR2 function (Chen X et al. J. Clin. Invest. 2014 Aug; 124(8):3295-310), and TGFBR2 is inactivated in a cancer cell line with p.Y470D as well as a second TGFBR2 substitution (p.K52T; Grady WM et al. Cancer Res. 1999 Jan; 59(2):320-4). Based on the supporting evidence, p.Y470D is interpreted as a disease-causing mutation.

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

From Invitae, SCV003482752.2

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr470 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26848186, 27879313; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 TGFBR2 protein function. ClinVar contains an entry for this variant (Variation ID: 217016). This missense change has been observed in individuals with clinical features of Loeys-Dietz syndrome (PMID: 25326637; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 470 of the TGFBR2 protein (p.Tyr470Asp).

#	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: Apr 20, 2024

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