NM_003242.6(TGFBR2):c.383del (p.Lys128fs) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 25, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000559144.17

Allele description [Variation Report for NM_003242.6(TGFBR2):c.383del (p.Lys128fs)]

NM_003242.6(TGFBR2):c.383del (p.Lys128fs)

Gene:

TGFBR2:transforming growth factor beta receptor 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

3p24.1

Genomic location:

Preferred name:

NM_003242.6(TGFBR2):c.383del (p.Lys128fs)

HGVS:

NC_000003.11:g.30691872del
NC_000003.12:g.30650389del
NG_007490.1:g.48888del
NM_001024847.3:c.458delA
NM_001407126.1:c.458delA
NM_001407127.1:c.383delA
NM_001407128.1:c.410delA
NM_001407129.1:c.278delA
NM_001407130.1:c.383delA
NM_001407132.1:c.278delA
NM_001407133.1:c.278delA
NM_001407134.1:c.278delA
NM_001407135.1:c.278delA
NM_001407136.1:c.278delA
NM_001407139.1:c.458delA
NM_003242.6:c.383delMANE SELECT
NP_001020018.1:p.Lys153Serfs
NP_001020018.1:p.Lys153fs
NP_001394055.1:p.Lys153Serfs
NP_001394056.1:p.Lys128Serfs
NP_001394057.1:p.Lys137Serfs
NP_001394058.1:p.Lys93Serfs
NP_001394059.1:p.Lys128Serfs
NP_001394061.1:p.Lys93Serfs
NP_001394062.1:p.Lys93Serfs
NP_001394063.1:p.Lys93Serfs
NP_001394064.1:p.Lys93Serfs
NP_001394065.1:p.Lys93Serfs
NP_001394068.1:p.Lys153Serfs
NP_003233.4:p.Lys128fs
LRG_779t1:c.458del
LRG_779t2:c.383del
LRG_779:g.48888del
LRG_779p1:p.Lys153fs
LRG_779p2:p.Lys128fs
NC_000003.11:g.30691872del
NC_000003.11:g.30691881del
NC_000003.11:g.30691881delA
NM_001024847.2:c.458del
NM_003242.5:c.383del
NM_003242.5:c.383delA

Protein change:

K128fs

Links:

dbSNP: rs79375991

NCBI 1000 Genomes Browser:

rs79375991

Molecular consequence:

NM_001024847.3:c.458delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407126.1:c.458delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407127.1:c.383delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407128.1:c.410delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407129.1:c.278delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407130.1:c.383delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407132.1:c.278delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407133.1:c.278delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407134.1:c.278delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407135.1:c.278delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407136.1:c.278delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407139.1:c.458delA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003242.6:c.383del - frameshift variant - [Sequence Ontology: SO:0001589]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000658831	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 25, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26948038, 28492532
SCV000739846	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Benign (May 6, 2020)	germline	clinical testing	Citation Link,
SCV001735851	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jun 25, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000658831

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 25, 2023)

germline

clinical testing

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

SCV000739846

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Benign
(May 6, 2020)

germline

clinical testing

Citation Link,

SCV001735851

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jun 25, 2020)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Successful Single-Stage Operation for Loeys-Dietz Syndrome With Critical Coarctation of the Descending Aorta in a Young Adult.

Wei S, Huang X, Hu S, Yang Y, Liu F.

Can J Cardiol. 2016 Oct;32(10):1260.e15-1260.e17. doi: 10.1016/j.cjca.2015.11.015. Epub 2015 Nov 23.

PubMed [citation]

PMID:: 26948038

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000658831.3

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

Description

This sequence change creates a premature translational stop signal (p.Lys128Serfs*35) in the TGFBR2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TGFBR2 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of Loeys-Dietz syndrome (PMID: 26948038). ClinVar contains an entry for this variant (Variation ID: 477546). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Ambry Genetics, SCV000739846.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

From Color Diagnostics, LLC DBA Color Health, SCV001735851.1

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

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

Last Updated: May 26, 2024

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