NM_004612.4(TGFBR1):c.409G>A (p.Val137Ile) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 22, 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:: RCV002321793.6

Allele description [Variation Report for NM_004612.4(TGFBR1):c.409G>A (p.Val137Ile)]

NM_004612.4(TGFBR1):c.409G>A (p.Val137Ile)

Gene:

TGFBR1:transforming growth factor beta receptor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q22.33

Genomic location:

Preferred name:

NM_004612.4(TGFBR1):c.409G>A (p.Val137Ile)

Other names:

p.V137I:GTC>ATC

HGVS:

NC_000009.12:g.99132574G>A
NG_007461.1:g.32445G>A
NM_001130916.3:c.343+3474G>A
NM_001306210.2:c.421G>A
NM_004612.4:c.409G>AMANE SELECT
NP_001293139.1:p.Val141Ile
NP_004603.1:p.Val137Ile
NC_000009.11:g.101894856G>A
NM_004612.2:c.409G>A

Protein change:

V137I

Links:

dbSNP: rs745576967

NCBI 1000 Genomes Browser:

rs745576967

Molecular consequence:

NM_001130916.3:c.343+3474G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001306210.2:c.421G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004612.4:c.409G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002632363	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 1, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003453525	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 20, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004362442	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 22, 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

SCV002632363

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 1, 2019)

germline

clinical testing

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

Citation Link,

SCV003453525

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 20, 2022)

germline

clinical testing

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

SCV004362442

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 22, 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

Marfan Syndrome Caused by Somatic Mosaicism in an FBN1 Splicing Mutation.

Rekondo J, Robledo-Inarritu M, Vado Y, Pérez de Nanclares G, Arós F.

Rev Esp Cardiol (Engl Ed). 2016 May;69(5):520-1. doi: 10.1016/j.rec.2016.01.018. Epub 2016 Mar 30. English, Spanish. No abstract available.

PubMed [citation]

PMID:: 27037046

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

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002632363.2

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

Description

The p.V137I variant (also known as c.409G>A), located in coding exon 3 of the TGFBR1 gene, results from a G to A substitution at nucleotide position 409. The valine at codon 137 is replaced by isoleucine, an amino acid with highly similar properties. This variant co-occurred with an FBN1 variant in a proband reported to have Marfan syndrome whose affected mother also carried the FBN1 variant, but not TGFBR1 p.V137I (Rekondo J et al. Rev Esp Cardiol (Engl Ed), 2016 May;69:520-1). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, 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 Invitae, SCV003453525.2

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

Description

This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. This variant is present in population databases (rs745576967, gnomAD 0.006%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 137 of the TGFBR1 protein (p.Val137Ile). ClinVar contains an entry for this variant (Variation ID: 213866). 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. 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 TGFBR1 protein function.

#	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 Color Diagnostics, LLC DBA Color Health, SCV004362442.1

#	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 valine with isoleucine at codon 137 of the TGFBR1 protein. Computational prediction suggests that this variant may have a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR1-related disorders in the literature. This variant has been identified in 6/251050 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

Last Updated: May 12, 2024

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