NM_004612.4(TGFBR1):c.944A>G (p.His315Arg) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 14, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000464356.6

Allele description [Variation Report for NM_004612.4(TGFBR1):c.944A>G (p.His315Arg)]

NM_004612.4(TGFBR1):c.944A>G (p.His315Arg)

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.944A>G (p.His315Arg)

HGVS:

NC_000009.12:g.99142674A>G
NG_007461.1:g.42545A>G
NM_001130916.3:c.713A>G
NM_001306210.2:c.956A>G
NM_004612.4:c.944A>GMANE SELECT
NP_001124388.1:p.His238Arg
NP_001293139.1:p.His319Arg
NP_004603.1:p.His315Arg
NC_000009.11:g.101904956A>G
NM_004612.2:c.944A>G

Protein change:

H238R

Links:

dbSNP: rs1060502045

NCBI 1000 Genomes Browser:

rs1060502045

Molecular consequence:

NM_001130916.3:c.713A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001306210.2:c.956A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004612.4:c.944A>G - 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
SCV000548340	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19542084, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000548340

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 14, 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

Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations.

Tran-Fadulu V, Pannu H, Kim DH, Vick GW 3rd, Lonsford CM, Lafont AL, Boccalandro C, Smart S, Peterson KL, Hain JZ, Willing MC, Coselli JS, LeMaire SA, Ahn C, Byers PH, Milewicz DM.

J Med Genet. 2009 Sep;46(9):607-13. doi: 10.1136/jmg.2008.062844. Epub 2009 Jun 18.

PubMed [citation]

PMID:: 19542084

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000548340.5

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

Description

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 315 of the TGFBR1 protein (p.His315Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR1-related conditions (PMID: 19542084; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 408569). 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 TGFBR1 protein function. For these reasons, this variant has been classified as Pathogenic.

#	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: Feb 28, 2024

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