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NM_003242.6(TGFBR2):c.1178G>A (p.Cys393Tyr) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Mar 22, 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:
RCV000253481.7

Allele description

NM_003242.6(TGFBR2):c.1178G>A (p.Cys393Tyr)

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.1178G>A (p.Cys393Tyr)
HGVS:
  • NC_000003.12:g.30672361G>A
  • NG_007490.1:g.70860G>A
  • NM_001024847.3:c.1253G>A
  • NM_001407126.1:c.1361G>A
  • NM_001407127.1:c.1286G>A
  • NM_001407128.1:c.1205G>A
  • NM_001407129.1:c.1181G>A
  • NM_001407130.1:c.1178G>A
  • NM_001407132.1:c.1073G>A
  • NM_001407133.1:c.1073G>A
  • NM_001407134.1:c.1073G>A
  • NM_001407135.1:c.1073G>A
  • NM_001407136.1:c.1073G>A
  • NM_001407137.1:c.893G>A
  • NM_001407138.1:c.818G>A
  • NM_003242.6:c.1178G>AMANE SELECT
  • NP_001020018.1:p.Cys418Tyr
  • NP_001020018.1:p.Cys418Tyr
  • NP_001394055.1:p.Cys454Tyr
  • NP_001394056.1:p.Cys429Tyr
  • NP_001394057.1:p.Cys402Tyr
  • NP_001394058.1:p.Cys394Tyr
  • NP_001394059.1:p.Cys393Tyr
  • NP_001394061.1:p.Cys358Tyr
  • NP_001394062.1:p.Cys358Tyr
  • NP_001394063.1:p.Cys358Tyr
  • NP_001394064.1:p.Cys358Tyr
  • NP_001394065.1:p.Cys358Tyr
  • NP_001394066.1:p.Cys298Tyr
  • NP_001394067.1:p.Cys273Tyr
  • NP_003233.4:p.Cys393Tyr
  • LRG_779t1:c.1253G>A
  • LRG_779t2:c.1178G>A
  • LRG_779:g.70860G>A
  • LRG_779p1:p.Cys418Tyr
  • LRG_779p2:p.Cys393Tyr
  • NC_000003.11:g.30713853G>A
  • NM_001024847.2:c.1253G>A
  • NM_003242.5:c.1178G>A
Protein change:
C273Y
Links:
dbSNP: rs886039106
NCBI 1000 Genomes Browser:
rs886039106
Molecular consequence:
  • NM_001024847.3:c.1253G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407126.1:c.1361G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407127.1:c.1286G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407128.1:c.1205G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407129.1:c.1181G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407130.1:c.1178G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407132.1:c.1073G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407133.1:c.1073G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407134.1:c.1073G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407135.1:c.1073G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407136.1:c.1073G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407137.1:c.893G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407138.1:c.818G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003242.6:c.1178G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000320065Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jul 6, 2017) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002991592Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Mar 22, 2022) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

TGFβ receptor mutations impose a strong predisposition for human allergic disease.

Frischmeyer-Guerrerio PA, Guerrerio AL, Oswald G, Chichester K, Myers L, Halushka MK, Oliva-Hemker M, Wood RA, Dietz HC.

Sci Transl Med. 2013 Jul 24;5(195):195ra94. doi: 10.1126/scitranslmed.3006448.

PubMed [citation]
PMID:
23884466
PMCID:
PMC3905327

International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium).

Jondeau G, Ropers J, Regalado E, Braverman A, Evangelista A, Teixedo G, De Backer J, Muiño-Mosquera L, Naudion S, Zordan C, Morisaki T, Morisaki H, Von Kodolitsch Y, Dupuis-Girod S, Morris SA, Jeremy R, Odent S, Adès LC, Bakshi M, Holman K, LeMaire S, Milleron O, et al.

Circ Cardiovasc Genet. 2016 Dec;9(6):548-558. doi: 10.1161/CIRCGENETICS.116.001485. Epub 2016 Nov 21.

PubMed [citation]
PMID:
27879313
PMCID:
PMC5177493
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000320065.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The p.C393Y pathogenic mutation (also known as c.1178G>A), located in coding exon 4 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1178. The cysteine at codon 393 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in a protein kinase domain. This alteration was confirmed as de novo in a proband whose clinical presentation is consistent with Loeys-Dietz syndrome (LDS). Another alteration at the same codon, p.C393G (c.1177T>G), has been observed in an individual with LDS (Frischmeyer-Guerrerio PA et al. Sci Transl Med 2013; 5(195):195ra94) and in a thoracic aortic disease cohort (Jondeau G et al. Circ Cardiovasc Genet, 2016 Dec;9:548-558); however, clinical details were limited. Based on the supporting evidence, p.C393Y is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV002991592.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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: 264260). This missense change has been observed in individual(s) with TGFBR2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 393 of the TGFBR2 protein (p.Cys393Tyr).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024