9-99149252-C-T

Position:

chr9-99149252-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 2.62

Variant links:

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]

TGFBR1 links:

TGFBR1 (HGNC:):

TGFBR1 links:

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ACMG classification

Classification made for transcript

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 gene, where missense usually causes diseases (based on misZ statistic), TGFBR1. . Gene score misZ 2.7935 (greater than the threshold 3.09). Trascript score misZ 3.6468 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4 linkuse as main transcript	c.1459C>T	p.Arg487Trp	missense_variant	9/9	ENST00000374994.9	NP_004603.1	P36897-1Q5T7S2B4DXN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9 linkuse as main transcript	c.1459C>T	p.Arg487Trp	missense_variant	9/9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	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). 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 25, 2018	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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 22, 2019	- -

Loeys-Dietz syndrome 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 24, 2021	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Loeys-Dietz syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 23, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 21, 2014

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

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

D;.;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.;.;.

PrimateAI

Pathogenic

0.93

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over