NM_003242.6(TGFBR2):c.1583G>A (p.Arg528His) AND Loeys-Dietz syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 29, 2014
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:: RCV000211858.5

Allele description [Variation Report for NM_003242.6(TGFBR2):c.1583G>A (p.Arg528His)]

NM_003242.6(TGFBR2):c.1583G>A (p.Arg528His)

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.1583G>A (p.Arg528His)

Other names:

p.R528H:CGT>CAT

HGVS:

NC_000003.12:g.30691478G>A
NG_007490.1:g.89977G>A
NM_001024847.3:c.1658G>A
NM_001407126.1:c.1766G>A
NM_001407127.1:c.1691G>A
NM_001407128.1:c.1610G>A
NM_001407129.1:c.1586G>A
NM_001407130.1:c.1580G>A
NM_001407132.1:c.1478G>A
NM_001407133.1:c.1478G>A
NM_001407134.1:c.1478G>A
NM_001407135.1:c.1478G>A
NM_001407136.1:c.1478G>A
NM_001407137.1:c.1298G>A
NM_001407138.1:c.1223G>A
NM_001407139.1:c.713G>A
NM_003242.6:c.1583G>AMANE SELECT
NP_001020018.1:p.Arg553His
NP_001020018.1:p.Arg553His
NP_001394055.1:p.Arg589His
NP_001394056.1:p.Arg564His
NP_001394057.1:p.Arg537His
NP_001394058.1:p.Arg529His
NP_001394059.1:p.Arg527His
NP_001394061.1:p.Arg493His
NP_001394062.1:p.Arg493His
NP_001394063.1:p.Arg493His
NP_001394064.1:p.Arg493His
NP_001394065.1:p.Arg493His
NP_001394066.1:p.Arg433His
NP_001394067.1:p.Arg408His
NP_001394068.1:p.Arg238His
NP_003233.4:p.Arg528His
LRG_779t1:c.1658G>A
LRG_779t2:c.1583G>A
LRG_779:g.89977G>A
LRG_779p1:p.Arg553His
LRG_779p2:p.Arg528His
NC_000003.11:g.30732970G>A
NM_001024847.2:c.1658G>A
NM_003242.5:c.1583G>A
P37173:p.Arg528His

Protein change:

R238H; ARG528HIS

Links:

UniProtKB: P37173#VAR_022361; OMIM: 190182.0011; dbSNP: rs104893815

NCBI 1000 Genomes Browser:

rs104893815

Molecular consequence:

NM_001024847.3:c.1658G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407126.1:c.1766G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407127.1:c.1691G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407128.1:c.1610G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407129.1:c.1586G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407130.1:c.1580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407132.1:c.1478G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407133.1:c.1478G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407134.1:c.1478G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407135.1:c.1478G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407136.1:c.1478G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407137.1:c.1298G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407138.1:c.1223G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407139.1:c.713G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003242.6:c.1583G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Loeys-Dietz syndrome (LDS)
Identifiers:: MONDO: MONDO:0018954; MedGen: C2697932; OMIM: PS609192

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000203966	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Aug 29, 2014)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15731757, 16928994, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000203966

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Aug 29, 2014)

germline

clinical testing

PubMed (3)
[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	not provided	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.

Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, et al.

Nat Genet. 2005 Mar;37(3):275-81. Epub 2005 Jan 30.

PubMed [citation]

PMID:: 15731757

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

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000203966.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

The Arg528His variant in TGFBR2 has been identified in >8 individuals with Loeys -Dietz syndrome and was found to occur de novo in one of these individuals (Loey s 2005, Loeys 2006, LMM unpublished data). It was absent from large population s tudies. In vitro and in vivo functional studies provide evidence that the Arg528 His variant may impact protein function. Computational prediction tools and cons ervation analysis suggest that the Arg528His variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

Last Updated: Feb 20, 2024

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