NM_003242.6(TGFBR2):c.913C>T (p.Leu305Phe) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 13, 2021
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:: RCV001857962.7

Allele description [Variation Report for NM_003242.6(TGFBR2):c.913C>T (p.Leu305Phe)]

NM_003242.6(TGFBR2):c.913C>T (p.Leu305Phe)

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.913C>T (p.Leu305Phe)

HGVS:

NC_000003.12:g.30672096C>T
NG_007490.1:g.70595C>T
NM_001024847.3:c.988C>T
NM_001407126.1:c.1096C>T
NM_001407127.1:c.1021C>T
NM_001407128.1:c.940C>T
NM_001407129.1:c.916C>T
NM_001407130.1:c.913C>T
NM_001407132.1:c.808C>T
NM_001407133.1:c.808C>T
NM_001407134.1:c.808C>T
NM_001407135.1:c.808C>T
NM_001407136.1:c.808C>T
NM_001407137.1:c.628C>T
NM_001407138.1:c.553C>T
NM_003242.6:c.913C>TMANE SELECT
NP_001020018.1:p.Leu330Phe
NP_001020018.1:p.Leu330Phe
NP_001394055.1:p.Leu366Phe
NP_001394056.1:p.Leu341Phe
NP_001394057.1:p.Leu314Phe
NP_001394058.1:p.Leu306Phe
NP_001394059.1:p.Leu305Phe
NP_001394061.1:p.Leu270Phe
NP_001394062.1:p.Leu270Phe
NP_001394063.1:p.Leu270Phe
NP_001394064.1:p.Leu270Phe
NP_001394065.1:p.Leu270Phe
NP_001394066.1:p.Leu210Phe
NP_001394067.1:p.Leu185Phe
NP_003233.4:p.Leu305Phe
LRG_779t1:c.988C>T
LRG_779t2:c.913C>T
LRG_779:g.70595C>T
LRG_779p1:p.Leu330Phe
LRG_779p2:p.Leu305Phe
NC_000003.11:g.30713588C>T
NM_001024847.2:c.988C>T
NM_003242.5:c.913C>T

Protein change:

L185F

Links:

dbSNP: rs1553630171

NCBI 1000 Genomes Browser:

rs1553630171

Molecular consequence:

NM_001024847.3:c.988C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407126.1:c.1096C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407127.1:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407128.1:c.940C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407129.1:c.916C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407130.1:c.913C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407132.1:c.808C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407133.1:c.808C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407134.1:c.808C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407135.1:c.808C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407136.1:c.808C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407137.1:c.628C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407138.1:c.553C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003242.6:c.913C>T - 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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hypothetical protein LOC84291 [Homo sapiens]
hypothetical protein LOC84291 [Homo sapiens]
gi|14150112|ref|NP_115707.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002170246	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 13, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29339704, 28492532
SCV002684798	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 13, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27139629, 29339704 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002170246

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 13, 2021)

germline

clinical testing

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

SCV002684798

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 13, 2021)

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002170246.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu305 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (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: 449834). This missense change has been observed in individual(s) with Loeys-Dietz syndrome (PMID: 29339704). 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 leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 305 of the TGFBR2 protein (p.Leu305Phe).

#	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

From Ambry Genetics, SCV002684798.2

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

Description

The p.L305F pathogenic mutation (also known as c.913C>T), located in coding exon 4 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 913. The leucine at codon 305 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been detected in two de novo cases with findings consistent with Loeys-Dietz syndrome (Ambry internal data; Kasar T et al. Anatol J Cardiol, 2018 Jan;19:74-77). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability and ligand binding (Tebben AJ et al. Acta Crystallogr D Struct Biol, 2016 05;72:658-74). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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