NM_004612.4(TGFBR1):c.1433A>G (p.Asn478Ser) AND Familial thoracic aortic aneurysm and aortic dissection

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Jan 29, 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:: RCV000229867.25

Allele description

NM_004612.4(TGFBR1):c.1433A>G (p.Asn478Ser)

Gene:

TGFBR1:transforming growth factor beta receptor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q22.33

Genomic location:

Preferred name:

NM_004612.4(TGFBR1):c.1433A>G (p.Asn478Ser)

Other names:

p.N478S:AAT>AGT

HGVS:

NC_000009.12:g.99149226A>G
NG_007461.1:g.49097A>G
NM_001130916.3:c.1202A>G
NM_001306210.2:c.1445A>G
NM_004612.4:c.1433A>GMANE SELECT
NP_001124388.1:p.Asn401Ser
NP_001293139.1:p.Asn482Ser
NP_004603.1:p.Asn478Ser
NC_000009.11:g.101911508A>G
NM_001130916.1:c.1202A>G
NM_004612.2:c.1433A>G
NM_004612.3:c.1433A>G

Protein change:

N401S

Links:

dbSNP: rs141259922

NCBI 1000 Genomes Browser:

rs141259922

Molecular consequence:

NM_001130916.3:c.1202A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001306210.2:c.1445A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004612.4:c.1433A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000288617	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16928994, 25116393, 25907466, 25985138, 28492532
SCV000319263	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Jan 13, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16928994, 24055113, 25116393, 25637381, 25907466, 25985138, 27153395 Citation Link,
SCV000913708	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 9, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 2511639, 16928994, 21358634, 25907466, 25985138, 28550590, 25741868
SCV002043332	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

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

Actionable, pathogenic incidental findings in 1,000 participants' exomes.

Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, Bennett RL, Jones KL, Tokita MJ, Bennett JT, Kim JH, Rosenthal EA, Kim DS; National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project., Tabor HK, Bamshad MJ, Motulsky AG, Scott CR, Pritchard CC, Walsh T, Burke W, Raskind WH, et al.

Am J Hum Genet. 2013 Oct 3;93(4):631-40. doi: 10.1016/j.ajhg.2013.08.006. Epub 2013 Sep 19.

PubMed [citation]

PMID:: 24055113
PMCID:: PMC3791261

See all PubMed Citations (12)

Details of each submission

From Invitae, SCV000288617.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 478 of the TGFBR1 protein (p.Asn478Ser). This variant is present in population databases (rs141259922, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Loeys-Dietz Syndrome (PMID: 16928994, 25116393, 25907466, 25985138). ClinVar contains an entry for this variant (Variation ID: 161393). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TGFBR1 protein function with a negative predictive value of 80%. 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, SCV000319263.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

The p.N478S variant (also known as c.1433A>G), located in coding exon 9 of the TGFBR1 gene, results from an A to G substitution at nucleotide position 1433. The asparagine at codon 478 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in Loeys-Dietz syndrome cohorts and thoracic aortic aneurysm and dissection (TAAD) cohorts; however, clinical details were limited in some cases (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98; Wellbrock J et al. PLoS ONE, 2014 Aug;9:e104742); Proost D et al. Hum. Mutat., 2015 Aug;36:808-14). This variant has also been seen in exome cohorts, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Taylor JC et al. Nat. Genet., 2015 Jul;47:717-726: Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-817). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Color Diagnostics, LLC DBA Color Health, SCV000913708.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces asparagine with serine at codon 478 of the TGFBR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Loeys-Dietz syndrome (PMID: 16928994, 2511639, 25985138), in individuals affected with Marfan-related disorders (PMID: 21358634, 25907466, 28550590) and in individuals affected with thoracic aortic aneurysm (PMID: 25907466, 28550590). This variant has been reported in an unaffected individual and his son showing a phenotype that is not consistent with Loeys-Dietz syndrome (Alsubaie 2018). This variant occurs at an appreciable frequency in the general population and has been identified in 77/281886 chromosomes (61/128464 non-Finnish European chromosomes) by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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 CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV002043332.2

#	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: Apr 20, 2024

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