NM_003242.6(TGFBR2):c.1189G>A (p.Asp397Asn) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 27, 2017
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:: RCV000253663.4

Allele description [Variation Report for NM_003242.6(TGFBR2):c.1189G>A (p.Asp397Asn)]

NM_003242.6(TGFBR2):c.1189G>A (p.Asp397Asn)

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.1189G>A (p.Asp397Asn)

HGVS:

NC_000003.12:g.30672372G>A
NG_007490.1:g.70871G>A
NM_001024847.3:c.1264G>A
NM_001407126.1:c.1372G>A
NM_001407127.1:c.1297G>A
NM_001407128.1:c.1216G>A
NM_001407129.1:c.1192G>A
NM_001407130.1:c.1189G>A
NM_001407132.1:c.1084G>A
NM_001407133.1:c.1084G>A
NM_001407134.1:c.1084G>A
NM_001407135.1:c.1084G>A
NM_001407136.1:c.1084G>A
NM_001407137.1:c.904G>A
NM_001407138.1:c.829G>A
NM_003242.6:c.1189G>AMANE SELECT
NP_001020018.1:p.Asp422Asn
NP_001020018.1:p.Asp422Asn
NP_001394055.1:p.Asp458Asn
NP_001394056.1:p.Asp433Asn
NP_001394057.1:p.Asp406Asn
NP_001394058.1:p.Asp398Asn
NP_001394059.1:p.Asp397Asn
NP_001394061.1:p.Asp362Asn
NP_001394062.1:p.Asp362Asn
NP_001394063.1:p.Asp362Asn
NP_001394064.1:p.Asp362Asn
NP_001394065.1:p.Asp362Asn
NP_001394066.1:p.Asp302Asn
NP_001394067.1:p.Asp277Asn
NP_003233.4:p.Asp397Asn
LRG_779t1:c.1264G>A
LRG_779t2:c.1189G>A
LRG_779:g.70871G>A
LRG_779p1:p.Asp422Asn
LRG_779p2:p.Asp397Asn
NC_000003.11:g.30713864G>A
NM_001024847.2:c.1264G>A
NM_003242.5:c.1189G>A

Protein change:

D277N

Links:

dbSNP: rs863223845

NCBI 1000 Genomes Browser:

rs863223845

Molecular consequence:

NM_001024847.3:c.1264G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407126.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407127.1:c.1297G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407128.1:c.1216G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407129.1:c.1192G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407130.1:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407132.1:c.1084G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407133.1:c.1084G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407134.1:c.1084G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407135.1:c.1084G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407136.1:c.1084G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407137.1:c.904G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407138.1:c.829G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003242.6:c.1189G>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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Krt36 keratin 36 [Mus musculus]
Krt36 keratin 36 [Mus musculus]
Gene ID:16673

Gene
16673[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000320314	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Dec 27, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25925954, 27139629 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000320314

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Dec 27, 2017)

germline

clinical testing

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

Citation Link

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

Phosphoryl Transfer Reaction Snapshots in Crystals: INSIGHTS INTO THE MECHANISM OF PROTEIN KINASE A CATALYTIC SUBUNIT.

Gerlits O, Tian J, Das A, Langan P, Heller WT, Kovalevsky A.

J Biol Chem. 2015 Jun 19;290(25):15538-15548. doi: 10.1074/jbc.M115.643213. Epub 2015 Apr 28.

PubMed [citation]

PMID:: 25925954
PMCID:: PMC4505467

Crystal structures of apo and inhibitor-bound TGFβR2 kinase domain: insights into TGFβR isoform selectivity.

Tebben AJ, Ruzanov M, Gao M, Xie D, Kiefer SE, Yan C, Newitt JA, Zhang L, Kim K, Lu H, Kopcho LM, Sheriff S.

Acta Crystallogr D Struct Biol. 2016 May;72(Pt 5):658-74. doi: 10.1107/S2059798316003624. Epub 2016 Apr 26.

PubMed [citation]

PMID:: 27139629

Details of each submission

From Ambry Genetics, SCV000320314.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.D397N variant (also known as c.1189G>A), located in coding exon 4 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1189. The aspartic acid at codon 397 is replaced by asparagine, an amino acid with highly similar properties. This alteration co-segregated with disease in one family tested at our laboratory. Internal structural analysis has revealed that the D397 residue is responsible for coordinating the Mg2+ of Mg-ATP during kinase activity (Tebben AJ et al. Acta Crystallogr D Struct Biol, 2016 05;72:658-74; Gerlits O et al. J. Biol. Chem., 2015 Jun;290:15538-48), and this alteration would likely result in a deleterious effect on the protein function. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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: May 1, 2024

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