NM_003242.6(TGFBR2):c.76C>T (p.Pro26Ser) AND Familial thoracic aortic aneurysm and aortic dissection

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 27, 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:: RCV001064639.9

Allele description

NM_003242.6(TGFBR2):c.76C>T (p.Pro26Ser)

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.76C>T (p.Pro26Ser)

HGVS:

NC_000003.12:g.30606959C>T
NG_007490.1:g.5458C>T
NM_001024847.3:c.76C>T
NM_001407126.1:c.76C>T
NM_001407127.1:c.76C>T
NM_001407130.1:c.76C>T
NM_001407133.1:c.-208C>T
NM_001407134.1:c.-86C>T
NM_001407135.1:c.-133C>T
NM_001407136.1:c.-218C>T
NM_001407137.1:c.76C>T
NM_001407138.1:c.76C>T
NM_001407139.1:c.76C>T
NM_003242.6:c.76C>TMANE SELECT
NP_001020018.1:p.Pro26Ser
NP_001020018.1:p.Pro26Ser
NP_001394055.1:p.Pro26Ser
NP_001394056.1:p.Pro26Ser
NP_001394059.1:p.Pro26Ser
NP_001394066.1:p.Pro26Ser
NP_001394067.1:p.Pro26Ser
NP_001394068.1:p.Pro26Ser
NP_003233.4:p.Pro26Ser
LRG_779t1:c.76C>T
LRG_779t2:c.76C>T
LRG_779:g.5458C>T
LRG_779p1:p.Pro26Ser
LRG_779p2:p.Pro26Ser
NC_000003.11:g.30648451C>T
NM_001024847.2:c.76C>T
NM_003242.5:c.76C>T

Protein change:

P26S

Links:

dbSNP: rs764160271

NCBI 1000 Genomes Browser:

rs764160271

Molecular consequence:

NM_001024847.3:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407126.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407127.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407130.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407137.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407138.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407139.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003242.6:c.76C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001229550	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001358262	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003912862	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 30, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001229550

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 22, 2021)

germline

clinical testing

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

SCV001358262

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 27, 2023)

germline

clinical testing

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

SCV003912862

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 30, 2022)

germline

clinical testing

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

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

Details of each submission

From Invitae, SCV001229550.3

#	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 proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 26 of the TGFBR2 protein (p.Pro26Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 858705). 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. 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

From Color Diagnostics, LLC DBA Color Health, SCV001358262.3

#	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 proline with serine at codon 26 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 4/252882 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, SCV003912862.2

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

Description

The p.P26S variant (also known as c.76C>T), located in coding exon 1 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 76. The proline at codon 26 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Last Updated: May 7, 2024

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