NM_003242.6(TGFBR2):c.340G>C (p.Glu114Gln) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 23, 2023
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:: RCV001190092.8

Allele description [Variation Report for NM_003242.6(TGFBR2):c.340G>C (p.Glu114Gln)]

NM_003242.6(TGFBR2):c.340G>C (p.Glu114Gln)

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.340G>C (p.Glu114Gln)

HGVS:

NC_000003.12:g.30650346G>C
NG_007490.1:g.48845G>C
NM_001024847.3:c.415G>C
NM_001407126.1:c.415G>C
NM_001407127.1:c.340G>C
NM_001407128.1:c.367G>C
NM_001407129.1:c.235G>C
NM_001407130.1:c.340G>C
NM_001407132.1:c.235G>C
NM_001407133.1:c.235G>C
NM_001407134.1:c.235G>C
NM_001407135.1:c.235G>C
NM_001407136.1:c.235G>C
NM_001407139.1:c.415G>C
NM_003242.6:c.340G>CMANE SELECT
NP_001020018.1:p.Glu139Gln
NP_001020018.1:p.Glu139Gln
NP_001394055.1:p.Glu139Gln
NP_001394056.1:p.Glu114Gln
NP_001394057.1:p.Glu123Gln
NP_001394058.1:p.Glu79Gln
NP_001394059.1:p.Glu114Gln
NP_001394061.1:p.Glu79Gln
NP_001394062.1:p.Glu79Gln
NP_001394063.1:p.Glu79Gln
NP_001394064.1:p.Glu79Gln
NP_001394065.1:p.Glu79Gln
NP_001394068.1:p.Glu139Gln
NP_003233.4:p.Glu114Gln
LRG_779t1:c.415G>C
LRG_779t2:c.340G>C
LRG_779:g.48845G>C
LRG_779p1:p.Glu139Gln
LRG_779p2:p.Glu114Gln
NC_000003.11:g.30691838G>C
NC_000003.11:g.30691838G>C
NM_001024847.2:c.415G>C
NM_003242.5:c.340G>C

Protein change:

E114Q

Links:

dbSNP: rs771551560

NCBI 1000 Genomes Browser:

rs771551560

Molecular consequence:

NM_001024847.3:c.415G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407126.1:c.415G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407127.1:c.340G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407128.1:c.367G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407129.1:c.235G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407130.1:c.340G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407132.1:c.235G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407133.1:c.235G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407134.1:c.235G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407135.1:c.235G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407136.1:c.235G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407139.1:c.415G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003242.6:c.340G>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001357507	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003998020	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 18, 2023)	germline	clinical testing	Citation Link,
SCV004279061	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 23, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001357507

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 1, 2023)

germline

clinical testing

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

SCV003998020

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 18, 2023)

germline

clinical testing

Citation Link,

SCV004279061

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 23, 2023)

germline

clinical testing

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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001357507.3

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

Description

This missense variant replaces glutamic acid with glutamine at codon 114 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has been identified in 1/250966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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, SCV003998020.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The c.340G>C (p.E114Q) alteration is located in exon 3 (coding exon 3) of the TGFBR2 gene. This alteration results from a G to C substitution at nucleotide position 340, causing the glutamic acid (E) at amino acid position 114 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004279061.1

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 114 of the TGFBR2 protein (p.Glu114Gln). This variant is present in population databases (rs771551560, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 927079). 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 not expected to disrupt TGFBR2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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