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NM_004612.4(TGFBR1):c.757A>G (p.Met253Val) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Feb 25, 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:
RCV001042584.15

Allele description [Variation Report for NM_004612.4(TGFBR1):c.757A>G (p.Met253Val)]

NM_004612.4(TGFBR1):c.757A>G (p.Met253Val)

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.757A>G (p.Met253Val)
HGVS:
  • NC_000009.12:g.99138041A>G
  • NG_007461.1:g.37912A>G
  • NM_001130916.3:c.526A>G
  • NM_001306210.2:c.769A>G
  • NM_004612.4:c.757A>GMANE SELECT
  • NP_001124388.1:p.Met176Val
  • NP_001293139.1:p.Met257Val
  • NP_004603.1:p.Met253Val
  • NC_000009.11:g.101900323A>G
  • NM_004612.2:c.757A>G
  • NM_004612.3:c.757A>G
Protein change:
M176V
Links:
dbSNP: rs886038919
NCBI 1000 Genomes Browser:
rs886038919
Molecular consequence:
  • NM_001130916.3:c.526A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306210.2:c.769A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004612.4:c.757A>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000319128Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely pathogenic
(Jul 7, 2020)
germlineclinical testing

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

Citation Link,

SCV001206274Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Feb 25, 2023)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels.

LaDuca H, Farwell KD, Vuong H, Lu HM, Mu W, Shahmirzadi L, Tang S, Chen J, Bhide S, Chao EC.

PLoS One. 2017;12(2):e0170843. doi: 10.1371/journal.pone.0170843.

PubMed [citation]
PMID:
28152038
PMCID:
PMC5289469

TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome.

Singh KK, Rommel K, Mishra A, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M.

Hum Mutat. 2006 Aug;27(8):770-7.

PubMed [citation]
PMID:
16799921
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000319128.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The p.M253V variant (also known as c.757A>G) is located in coding exon 4 of the TGFBR1 gene in the protein kinase domain. This alteration results from an A to G substitution at nucleotide position 757. The methionine at codon 253 is replaced by valine, an amino acid with some highly similar properties, and is located in a protein kinase domain. This variant has been identified in an individual with Loeys-Dietz syndrome symptoms (Ambry internal data). Another alteration at the same codon, p.M253I (c.759G>A) has been reported in individuals with Marfan syndrome and Loeys-Dietz syndrome, with segregation of disease reported in at least one family (Singh KK et al. Hum. Mutat., 2006 Aug;27:770-7; Stheneur C et al. Hum. Mutat., 2008 Nov;29:E284-95; Söylen B et al. Clin. Genet., 2009 Mar;75:265-70; Beckmann E et al. Ann. Thorac. Surg., 2014 May;97:e125-7; Jondeau G et al. Circ Cardiovasc Genet, 2016 Dec;9:548-558). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001206274.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This variant disrupts the p.Met253 amino acid residue in TGFBR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16799921, 18781618, 31624717). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 253 of the TGFBR1 protein (p.Met253Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TGFBR1-related conditions (Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 263773). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024