NM_003242.6(TGFBR2):c.1043G>A (p.Arg348His) AND Familial thoracic aortic aneurysm and aortic dissection

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

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 28, 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:: RCV000809072.8

Allele description

NM_003242.6(TGFBR2):c.1043G>A (p.Arg348His)

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.1043G>A (p.Arg348His)

HGVS:

NC_000003.12:g.30672226G>A
NG_007490.1:g.70725G>A
NM_001024847.3:c.1118G>A
NM_001407126.1:c.1226G>A
NM_001407127.1:c.1151G>A
NM_001407128.1:c.1070G>A
NM_001407129.1:c.1046G>A
NM_001407130.1:c.1043G>A
NM_001407132.1:c.938G>A
NM_001407133.1:c.938G>A
NM_001407134.1:c.938G>A
NM_001407135.1:c.938G>A
NM_001407136.1:c.938G>A
NM_001407137.1:c.758G>A
NM_001407138.1:c.683G>A
NM_003242.6:c.1043G>AMANE SELECT
NP_001020018.1:p.Arg373His
NP_001020018.1:p.Arg373His
NP_001394055.1:p.Arg409His
NP_001394056.1:p.Arg384His
NP_001394057.1:p.Arg357His
NP_001394058.1:p.Arg349His
NP_001394059.1:p.Arg348His
NP_001394061.1:p.Arg313His
NP_001394062.1:p.Arg313His
NP_001394063.1:p.Arg313His
NP_001394064.1:p.Arg313His
NP_001394065.1:p.Arg313His
NP_001394066.1:p.Arg253His
NP_001394067.1:p.Arg228His
NP_003233.4:p.Arg348His
LRG_779t1:c.1118G>A
LRG_779t2:c.1043G>A
LRG_779:g.70725G>A
LRG_779p1:p.Arg373His
LRG_779p2:p.Arg348His
NC_000003.11:g.30713718G>A
NM_001024847.2:c.1118G>A
NM_003242.5:c.1043G>A

Protein change:

R228H

Links:

dbSNP: rs369450067

NCBI 1000 Genomes Browser:

rs369450067

Molecular consequence:

NM_001024847.3:c.1118G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407126.1:c.1226G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407127.1:c.1151G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407128.1:c.1070G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407129.1:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407130.1:c.1043G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407132.1:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407133.1:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407134.1:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407135.1:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407136.1:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407137.1:c.758G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407138.1:c.683G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003242.6:c.1043G>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

Recent activity

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hypothetical protein [Archaeoglobus sulfaticallidus]
hypothetical protein [Archaeoglobus sulfaticallidus]
gi|505403536|ref|WP_015590638.1|

Protein
tyrosine--tRNA ligase [Synechococcus sp. PCC 7502]
tyrosine--tRNA ligase [Synechococcus sp. PCC 7502]
gi|504980972|ref|WP_015168074.1|

Protein
hypothetical protein [Calothrix sp. PCC 7507]
hypothetical protein [Calothrix sp. PCC 7507]
gi|504942691|ref|WP_015129793.1|

Protein
EBENXNS02IPK0Z 8-day Arabidopsis seedlings, aerial tissues Arabidopsis thaliana ...
EBENXNS02IPK0Z 8-day Arabidopsis seedlings, aerial tissues Arabidopsis thaliana cDNA, mRNA sequence
gi|124892329|gnl|dbEST|44365293|gb| 231.1|

Nucleotide
Homo sapiens pantothenate kinase 4, mRNA (cDNA clone MGC:49883 IMAGE:5244472), c...
Homo sapiens pantothenate kinase 4, mRNA (cDNA clone MGC:49883 IMAGE:5244472), complete cds
gi|28175374|gb|BC043496.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000949211	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18781618, 28492532
SCV001354469	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18781618, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000949211

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 28, 2023)

germline

clinical testing

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

SCV001354469

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 20, 2023)

germline

clinical testing

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

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

Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders.

Stheneur C, Collod-Béroud G, Faivre L, Gouya L, Sultan G, Le Parc JM, Moura B, Attias D, Muti C, Sznajder M, Claustres M, Junien C, Baumann C, Cormier-Daire V, Rio M, Lyonnet S, Plauchu H, Lacombe D, Chevallier B, Jondeau G, Boileau C.

Hum Mutat. 2008 Nov;29(11):E284-95. doi: 10.1002/humu.20871.

PubMed [citation]

PMID:: 18781618

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000949211.4

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

Description

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 TGFBR2 protein function. ClinVar contains an entry for this variant (Variation ID: 432420). This missense change has been observed in individual(s) with clinical features of TGFBR2-related disease (PMID: 18781618). This variant is present in population databases (rs369450067, gnomAD 0.008%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 348 of the TGFBR2 protein (p.Arg348His).

#	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, SCV001354469.3

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

Description

This missense variant replaces arginine with histidine at codon 348 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 been reported in one individual suspected with Marfan syndrome or related disorders (PMID: 18781618). This variant has been identified in 10/280264 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 7, 2024

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