NM_003242.6(TGFBR2):c.1562G>A (p.Trp521Ter) AND Loeys-Dietz syndrome 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 23, 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:: RCV003153131.1

Allele description [Variation Report for NM_003242.6(TGFBR2):c.1562G>A (p.Trp521Ter)]

NM_003242.6(TGFBR2):c.1562G>A (p.Trp521Ter)

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.1562G>A (p.Trp521Ter)

HGVS:

NC_000003.12:g.30691457G>A
NG_007490.1:g.89956G>A
NM_001024847.3:c.1637G>A
NM_001407126.1:c.1745G>A
NM_001407127.1:c.1670G>A
NM_001407128.1:c.1589G>A
NM_001407129.1:c.1565G>A
NM_001407130.1:c.1559G>A
NM_001407132.1:c.1457G>A
NM_001407133.1:c.1457G>A
NM_001407134.1:c.1457G>A
NM_001407135.1:c.1457G>A
NM_001407136.1:c.1457G>A
NM_001407137.1:c.1277G>A
NM_001407138.1:c.1202G>A
NM_001407139.1:c.692G>A
NM_003242.6:c.1562G>AMANE SELECT
NP_001020018.1:p.Trp546Ter
NP_001020018.1:p.Trp546Ter
NP_001394055.1:p.Trp582Ter
NP_001394056.1:p.Trp557Ter
NP_001394057.1:p.Trp530Ter
NP_001394058.1:p.Trp522Ter
NP_001394059.1:p.Trp520Ter
NP_001394061.1:p.Trp486Ter
NP_001394062.1:p.Trp486Ter
NP_001394063.1:p.Trp486Ter
NP_001394064.1:p.Trp486Ter
NP_001394065.1:p.Trp486Ter
NP_001394066.1:p.Trp426Ter
NP_001394067.1:p.Trp401Ter
NP_001394068.1:p.Trp231Ter
NP_003233.4:p.Trp521Ter
LRG_779t1:c.1637G>A
LRG_779t2:c.1562G>A
LRG_779:g.89956G>A
LRG_779p1:p.Trp546Ter
LRG_779p2:p.Trp521Ter
NC_000003.11:g.30732949G>A
NM_001024847.2:c.1637G>A

Protein change:

W231*

Molecular consequence:

NM_001024847.3:c.1637G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407126.1:c.1745G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407127.1:c.1670G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407128.1:c.1589G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407129.1:c.1565G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407130.1:c.1559G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407132.1:c.1457G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407133.1:c.1457G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407134.1:c.1457G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407135.1:c.1457G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407136.1:c.1457G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407137.1:c.1277G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407138.1:c.1202G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001407139.1:c.692G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_003242.6:c.1562G>A - nonsense - [Sequence Ontology: SO:0001587]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003841942	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18781618, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003841942

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 23, 2023)

unknown

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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders.

Stheneur C, Collod-Béroud G, Faivre L, Gouya L, Sultan G, Le Parc JM, Moura B, Attias D, Muti C, Sznajder M, Claustres M, Junien C, Baumann C, Cormier-Daire V, Rio M, Lyonnet S, Plauchu H, Lacombe D, Chevallier B, Jondeau G, Boileau C.

Hum Mutat. 2008 Nov;29(11):E284-95. doi: 10.1002/humu.20871.

PubMed [citation]

PMID:: 18781618

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From 3billion, SCV003841942.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 18781618). The variant has been reported to be associated with TGFBR2 -related disorder (PMID: 18781618). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Mar 26, 2023

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