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NM_003242.6(TGFBR2):c.1378C>T (p.Arg460Cys) AND Loeys-Dietz syndrome 2

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Nov 28, 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:
RCV000013339.26

Allele description [Variation Report for NM_003242.6(TGFBR2):c.1378C>T (p.Arg460Cys)]

NM_003242.6(TGFBR2):c.1378C>T (p.Arg460Cys)

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.1378C>T (p.Arg460Cys)
Other names:
p.R460C:CGC>TGC
HGVS:
  • NC_000003.12:g.30674228C>T
  • NG_007490.1:g.72727C>T
  • NM_001024847.3:c.1453C>T
  • NM_001407126.1:c.1561C>T
  • NM_001407127.1:c.1486C>T
  • NM_001407128.1:c.1405C>T
  • NM_001407129.1:c.1381C>T
  • NM_001407130.1:c.1378C>T
  • NM_001407132.1:c.1273C>T
  • NM_001407133.1:c.1273C>T
  • NM_001407134.1:c.1273C>T
  • NM_001407135.1:c.1273C>T
  • NM_001407136.1:c.1273C>T
  • NM_001407137.1:c.1093C>T
  • NM_001407138.1:c.1018C>T
  • NM_003242.6:c.1378C>TMANE SELECT
  • NP_001020018.1:p.Arg485Cys
  • NP_001020018.1:p.Arg485Cys
  • NP_001394055.1:p.Arg521Cys
  • NP_001394056.1:p.Arg496Cys
  • NP_001394057.1:p.Arg469Cys
  • NP_001394058.1:p.Arg461Cys
  • NP_001394059.1:p.Arg460Cys
  • NP_001394061.1:p.Arg425Cys
  • NP_001394062.1:p.Arg425Cys
  • NP_001394063.1:p.Arg425Cys
  • NP_001394064.1:p.Arg425Cys
  • NP_001394065.1:p.Arg425Cys
  • NP_001394066.1:p.Arg365Cys
  • NP_001394067.1:p.Arg340Cys
  • NP_003233.4:p.Arg460Cys
  • LRG_779t1:c.1453C>T
  • LRG_779t2:c.1378C>T
  • LRG_779:g.72727C>T
  • LRG_779p1:p.Arg485Cys
  • LRG_779p2:p.Arg460Cys
  • NC_000003.11:g.30715720C>T
  • NM_001024847.2:c.1453C>T
  • NM_003242.5:c.1378C>T
  • P37173:p.Arg460Cys
Protein change:
R340C; ARG460CYS
Links:
UniProtKB: P37173#VAR_029760; OMIM: 190182.0014; dbSNP: rs104893811
NCBI 1000 Genomes Browser:
rs104893811
Molecular consequence:
  • NM_001024847.3:c.1453C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407126.1:c.1561C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407127.1:c.1486C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407128.1:c.1405C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407129.1:c.1381C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407130.1:c.1378C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407132.1:c.1273C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407133.1:c.1273C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407134.1:c.1273C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407135.1:c.1273C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407136.1:c.1273C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407137.1:c.1093C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407138.1:c.1018C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003242.6:c.1378C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Loeys-Dietz syndrome 2 (LDS2)
Synonyms:
Loeys-Dietz syndrome type 1B; MARFAN SYNDROME, TYPE II; Loeys-Dietz syndrome type 2B; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0012427; MedGen: C2674574; Orphanet: 558; OMIM: 610168

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000033586OMIM
no assertion criteria provided
Pathogenic
(Jul 26, 2005)
germlineliterature only

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

SCV004839378All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 28, 2023)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

Mapping a locus for familial thoracic aortic aneurysms and dissections (TAAD2) to 3p24-25.

Hasham SN, Willing MC, Guo DC, Muilenburg A, He R, Tran VT, Scherer SE, Shete SS, Milewicz DM.

Circulation. 2003 Jul 1;107(25):3184-90. Epub 2003 Jun 23.

PubMed [citation]
PMID:
12821554

Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections.

Pannu H, Fadulu VT, Chang J, Lafont A, Hasham SN, Sparks E, Giampietro PF, Zaleski C, Estrera AL, Safi HJ, Shete S, Willing MC, Raman CS, Milewicz DM.

Circulation. 2005 Jul 26;112(4):513-20. Epub 2005 Jul 18.

PubMed [citation]
PMID:
16027248
See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000033586.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In 2 families with thoracic aortic aneurysm and dissection mapping to chromosome 3p25-p24 (LDS2; 610168), Pannu et al. (2005) detected a 1378C-T transition in exon 5 of the TGFBR2 gene that resulted in the substitution of cysteine for arginine at amino acid 460 (R460C). The clinical features of one of these families had been reported by Hasham et al. (2003). The proband of the second family, a 4-generation family with autosomal dominant thoracic aortic aneurysm and dissection, presented at 41 years of age with an aneurysm of the ascending aorta and mitral valve prolapse. Affected members of the family presented primarily with type A dissections.

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

From All of Us Research Program, National Institutes of Health, SCV004839378.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

This variant has been reported in multiple individuals with thoracic aortic aneurysm and dissection (TAAD), and it has been reported to co-segregate with TAAD in multiple families (PMID: 16799921, 16027248, 19159394, 19542084). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). It is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 21098638). A different missense substitution at this amino acid residue, p.Arg460His, has been previously reported in individuals with TAAD and Loeys-Dietz syndrome, and it is classified as pathogenic (ClinVar variation ID 12515), which supports the functional importance of this position.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024