9-99149252-C-T

Variant names:

• chr9-99149252-C-T
• rs111426349
• NM_004612.4:c.1459C>T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004612.4(TGFBR1):​c.1459C>T​(p.Arg487Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R487Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 2.62

Genes affected

TGFBR1 (HGNC:11772): (transforming growth factor beta receptor 1) The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain Protein kinase (size 290) in uniprot entity TGFR1_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in NM_004612.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-99149253-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in the TGFBR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 2.7935 (below the threshold of 3.09). Trascript score misZ: 3.6468 (above the threshold of 3.09). GenCC associations: The gene is linked to familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome, multiple self-healing squamous epithelioma, Loeys-Dietz syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 9-99149252-C-T is Pathogenic according to our data. Variant chr9-99149252-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99149252-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.1459C>T	p.Arg487Trp	missense_variant	Exon 9 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.1459C>T	p.Arg487Trp	missense_variant	Exon 9 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:4

Oct 04, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 04, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 478 in the cytoplasmic kinase domain of the TGFBR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported to segregate with thoracic aortic aneurysm and dissections in over ten individuals from two large families (PMID: 19542084, 25110237). This variant has been observed in individuals affected with Loeys-Dietz syndrome (PMID: 16928994, 23884466, 26848186, 26877057), aortopathy (PMID: 27611364) and Marfan syndrome (PMID: 24793577). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg487Gln, is known to be disease-causing, indicating the importance of arginine residue at this position for TGFBR1 protein function (ClinVar variation ID: 12525). Based on the available evidence, this variant is classified as Pathogenic. -

Apr 25, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R487W pathogenic mutation (also known as c.1459C>T), located in coding exon 9 of the TGFBR1 gene, results from a C to T substitution at nucleotide position 1459. The arginine at codon 487 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in association with Loeys Dietz syndrome, thoracic aortic aneurysm and dissection, as well as other aortic disease (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98; Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6; Yang H et al. Sci Rep, 2016 Sep;6:33002; Luo M et al. Clin. Chim. Acta, 2016 May;456:144-148). In addition, this alteration segregated with the disease in a few apparently unrelated families (Tran-Fadulu V et al. J. Med. Genet., 2009 Sep;46:607-13; Dong SB et al. Ann Vasc Surg, 2014 Nov;28:1909-12; Teixidó-Tura G et al. Heart, 2016 Apr;102:626-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 487 of the TGFBR1 protein (p.Arg487Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Loeys-Dietz syndrome and thoracic aortic aneurysm and dissections (PMID: 19542084, 23884466, 24793577, 25110237, 27611364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12526). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TGFBR1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg487 amino acid residue in TGFBR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23884466). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Loeys-Dietz syndrome 1 Pathogenic:3

Sep 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 24, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PP2+PS4+PP4+PP1_Strong -

not provided Pathogenic:3

Feb 07, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple unrelated individuals with Loeys-Dietz syndrome, isolated thoracic aortic aneurysm and dissection (TAAD) or aortic disease, and possible Marfan syndrome in the published literature (Loeys et al., 2006; Tran-Fadulu et al., 2009; Dong et al., 2014; Luo et al., 2016; Teixido-Tura et al., 2016; Yang et al., 2016; Zheng et al., 2018; Jani et al., 2020; Li et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16928994, 30341550, 24793577, 21815248, 23884466, 26877057, 27611364, 26848186, 27879313, 21358634, 29510914, 30056620, 34456093, 34150014, 30513140, 30787465, 32152251, 34916229, 25110237, 19542084) -

Multiple self-healing squamous epithelioma;C4551955:Loeys-Dietz syndrome 1 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome Pathogenic:1

Jul 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 478 in the cytoplasmic kinase domain of the TGFBR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported to segregate with thoracic aortic aneurysm and dissections in over ten individuals from two large families (PMID: 19542084, 25110237). This variant has been observed in individuals affected with Loeys-Dietz syndrome (PMID: 16928994, 23884466, 26848186, 26877057), aortopathy (PMID: 27611364) and Marfan syndrome (PMID: 24793577). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg487Gln, is known to be disease-causing, indicating the importance of arginine residue at this position for TGFBR1 protein function (ClinVar variation ID: 12525). Based on the available evidence, this variant is classified as Pathogenic. -

Loeys-Dietz syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Aug 21, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg487Trp variant in TGFBR1 has been reported in 4 individuals with clinical features of Loeys-Dietz syndrome (Loeys 2006, Frischmeyer-Guerrerio 2013, LMM u npublished). Additionally, the Arg487Trp variant was reported in 3 individuals w ith familial thoracic aortic aneurysm and dissection (TAAD) and segregated with disease in 13 affected relatives with TAAD from two of these families (Tran-Fadu lu 2009, Aragon-Martin 2013, Dong 2014). This variant was absent from large popu lation studies. Computational prediction tools and conservation analysis suggest that the Arg487Trp variant may impact the protein, though this information is n ot predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.2	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.89
MutPred		0.94		Gain of ubiquitination at K490 (P = 0.0289);.;.;.;
MVP		0.97
MPC		1.7
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.97
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111426349; hg19: chr9-101911534; COSMIC: COSV66625981; COSMIC: COSV66625981;