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NM_003242.6(TGFBR2):c.1483C>T (p.Arg495Ter) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Nov 3, 2024
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:
RCV000253575.14

Allele description [Variation Report for NM_003242.6(TGFBR2):c.1483C>T (p.Arg495Ter)]

NM_003242.6(TGFBR2):c.1483C>T (p.Arg495Ter)

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.1483C>T (p.Arg495Ter)
Other names:
p.R495*:CGA>TGA
HGVS:
  • NC_000003.12:g.30688470C>T
  • NG_007490.1:g.86969C>T
  • NM_001024847.3:c.1558C>T
  • NM_001407126.1:c.1666C>T
  • NM_001407127.1:c.1591C>T
  • NM_001407128.1:c.1510C>T
  • NM_001407129.1:c.1486C>T
  • NM_001407130.1:c.1480C>T
  • NM_001407132.1:c.1378C>T
  • NM_001407133.1:c.1378C>T
  • NM_001407134.1:c.1378C>T
  • NM_001407135.1:c.1378C>T
  • NM_001407136.1:c.1378C>T
  • NM_001407137.1:c.1198C>T
  • NM_001407138.1:c.1123C>T
  • NM_001407139.1:c.613C>T
  • NM_003242.6:c.1483C>TMANE SELECT
  • NP_001020018.1:p.Arg520Ter
  • NP_001020018.1:p.Arg520Ter
  • NP_001394055.1:p.Arg556Ter
  • NP_001394056.1:p.Arg531Ter
  • NP_001394057.1:p.Arg504Ter
  • NP_001394058.1:p.Arg496Ter
  • NP_001394059.1:p.Arg494Ter
  • NP_001394061.1:p.Arg460Ter
  • NP_001394062.1:p.Arg460Ter
  • NP_001394063.1:p.Arg460Ter
  • NP_001394064.1:p.Arg460Ter
  • NP_001394065.1:p.Arg460Ter
  • NP_001394066.1:p.Arg400Ter
  • NP_001394067.1:p.Arg375Ter
  • NP_001394068.1:p.Arg205Ter
  • NP_003233.4:p.Arg495Ter
  • LRG_779t1:c.1558C>T
  • LRG_779t2:c.1483C>T
  • LRG_779:g.86969C>T
  • LRG_779p1:p.Arg520Ter
  • LRG_779p2:p.Arg495Ter
  • NC_000003.11:g.30729962C>T
  • NM_001024847.2:c.1558C>T
  • NM_003242.5:c.1483C>T
Protein change:
R205*; ARG495TER
Links:
OMIM: 190182.0019; dbSNP: rs104893819
NCBI 1000 Genomes Browser:
rs104893819
Molecular consequence:
  • NM_001024847.3:c.1558C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407126.1:c.1666C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407127.1:c.1591C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407128.1:c.1510C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407129.1:c.1486C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407130.1:c.1480C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407132.1:c.1378C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407133.1:c.1378C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407134.1:c.1378C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407135.1:c.1378C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407136.1:c.1378C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407137.1:c.1198C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407138.1:c.1123C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001407139.1:c.613C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_003242.6:c.1483C>T - nonsense - [Sequence Ontology: SO:0001587]

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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000319544Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(May 15, 2023) 		germlineclinical testing

Citation Link,

SCV000658821Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 3, 2024) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Aneurysm syndromes caused by mutations in the TGF-beta receptor.

Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC.

N Engl J Med. 2006 Aug 24;355(8):788-98.

PubMed [citation]
PMID:
16928994

Phenotypic heterogeneity of Marfan-like connective tissue disorders associated with mutations in the transforming growth factor-beta receptor genes.

Akutsu K, Morisaki H, Takeshita S, Sakamoto S, Tamori Y, Yoshimuta T, Yokoyama N, Nonogi H, Ogino H, Morisaki T.

Circ J. 2007 Aug;71(8):1305-9.

PubMed [citation]
PMID:
17652900
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000319544.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.R495* pathogenic mutation (also known as c.1483C>T), located in coding exon 6 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1483. This changes the amino acid from an arginine to a stop codon within coding exon 6. This alteration occurs at the 3' terminus of theTGFBR2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 12.8% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in several individuals and families with a diagnosis of Loeys-Dietz syndrome (Loeys et al. N Engl J Med. 2006;355(8):788-98; Togashi et al. Intern Med. 2007;46(24):1995-2000; Yang et al. J Hum Genet. 2012;57:52-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000658821.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Arg495*) in the TGFBR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the TGFBR2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Loeys-Dietz syndrome (PMID: 16928994, 17652900, 18084123, 22113417). ClinVar contains an entry for this variant (Variation ID: 12519). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Feb 25, 2025