rs113605875

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_004612.4(TGFBR1):c.1460G>A(p.Arg487Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R487W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

TGFBR1
NM_004612.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 10.0

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:

Genome browser will be placed here

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 chr9-99149252-C-T 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, 0.968

PP5

Variant 9-99149253-G-A is Pathogenic according to our data. Variant chr9-99149253-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99149253-G-A is described in Lovd as [Pathogenic]. Variant chr9-99149253-G-A 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.1460G>A	p.Arg487Gln	missense_variant	9/9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9 linkuse as main transcript	c.1460G>A	p.Arg487Gln	missense_variant	9/9	1	NM_004612.4	ENSP00000364133	P4	P36897-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Loeys-Dietz syndrome 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 20, 2021	ACMG classification criteria: PS2 strong, PS3 supporting, PS4 moderate, PM2 moderate, PM5, PP3 supporting -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Nov 01, 2023	PS4, PM1, PM2, PM5, PP3, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 527177). This variant has been previously reported as causative for Marfan syndrome. (PMID:25652356). -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene. In addition, missense variants have been postulated to exert a dominant negative effect. Both mechanisms are associated with Loeys-Dietz syndrome (MIM#609192) (PMID: 30701076). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Several pathogenic variants have been reported for codons 486 and 487 (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least ten patients with Loeys-Dietz syndrome, with a single case of maternal mosaicism (Clinvar; PMID: 16928994, 16791849, 22113417, 25116393, 30219046). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 487 of the TGFBR1 protein (p.Arg487Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Loeys-Dietz syndrome (PMID: 16791849, 18455604; 22113417and23884466). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12525). 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%. Experimental studies have shown that this missense change affects TGFBR1 function (PMID: 21358634). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: 15731757, 16928994, 22414221, 23884466, 25110237). 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	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 09, 2018	The p.R487Q pathogenic mutation (also known as c.1460G>A), located in coding exon 9 of the TGFBR1 gene, results from a G to A substitution at nucleotide position 1460. The arginine at codon 487 is replaced by glutamine, an amino acid with highly similar properties, and is located in the protein kinase domain. This alteration has been reported in multiple individuals reported to have Loeys-Dietz syndrome (LDS) and related features (Loeys BL et al. N Engl J Med. 2006;355:788-98; Akutsu K et al. Circ J. 2007;71:1305-9; Melenovsky V et al. J Thorac Cardiovasc Surg. 2008;135:1174-5,1175.e1; Yang JH et al. J Hum Genet. 2012;57:52-6; Wang C et al. Chin Med J. 2014;127:2398-9; Ting TW et al. Eur J Pediatr. 2014;173(3):387-91; Pieroni A et al. Intern Emerg Med. 2015;10:165-70). In addition, this alteration was reported as a de novo occurrence in an individual with aortic dissection (Mátyás G et al. Hum Mutat. 2006;27:760-9), and has been reported to result in altered protein function (Goudie DR et al. Nat Genet. 2011;43:365-9). Other alterations affecting this amino acid (p.R487W, p.R487P, and p.R487G) have also been reported in association with LDS or detected in LDS cohorts (Loeys BL et al. N Engl J Med. 2006;355:788-98; Frischmeyer-Guerrerio PA et al. Sci Transl Med. 2013;5(195):195ra94). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TGFBR1: PM1, PM2, PM5, PM6, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate reduced elastin and fibulin 1 expression, impaired deposition of elastic fibers, and impaired TGF-beta signaling (Barnett et al., 2011; Goudie et al., 2011); 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: 23884466, 27879313, 22113417, 21267002, 17061023, 24146167, 16928994, 18455604, 25116393, 17652900, 21358634, 29907982, 24931266, 30219046, 31915033, 32352226, 16791849) -

Loeys-Dietz syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 26, 2019

Variant summary: TGFBR1 c.1460G>A (p.Arg487Gln) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250796 control chromosomes (gnomAD). c.1460G>A has been reported in the literature, including de novo occurrences, in multiple individuals affected with Loeys-Dietz Syndrome, acute aortic dissection and thoracic aortic aneurysms (Loeys_2006, Matyas_2006, Akutsu_2007, Yang_2012). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to result in decreased expression and impaired deposition of elastic fibers, while it also causes decreased TGF-beta signaling (Barnett_2011, Goudie_2011). Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

TGFBR1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2024

The TGFBR1 c.1460G>A variant is predicted to result in the amino acid substitution p.Arg487Gln. This variant has been reported in individuals with Loeys-Dietz syndrome type 1 and thoracic aortic aneurysms and dissections (TAAD) (Matyas et al. 2006. PubMed ID: 16791849; Melenovsky et al. 2008. PubMed ID: 18455604; Yang et al. 2011. PubMed ID: 22113417). This variant, in addition to other variants impacting this same amino acid (p.Arg487Trp and p.Arg487Gly) have been reported in individuals with allergic disease, however specific details were not provided (Supplementary Table 1, Frischmeyer-Guerrerio et al. 2013. PubMed ID: 23884466). In addition, other variants impacting the p.Arg487 amino acid have been reported in individuals with Loeys-Dietz syndrome type 1 (p.Arg487Trp, Loeys et al. 2006. PubMed ID: 16928994; p.Arg487Pro, Loeys et al. 2005. PubMed ID: 15731757). Functional studies have shown that this variant impacts TGFBR1 protein function (Goudie et al. 2011. PubMed ID: 21358634). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted 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 19, 2014

The Arg487Gln variant (TGFBR1) has been reported in the literature in six indivi duals with clinical features of Loeys-Dietz syndrome, with de novo occurrence of the variant confirmed in two of the probands (Loeys 2006, Matyas 2006, Melenovs ky 2008, Yang 2012). In addition, functional analyses revealed that the mutant p rotein alters the normal function of the TGFBR1 protein (Barnett 2011, Goudie 20 11). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon de novo occurrence in symptomatic ind ividuals and observed functional effect of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.42

T;.;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.5

L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.85

MutPred

0.90

Gain of ubiquitination at K490 (P = 0.0338);.;.;.;

MVP

0.99

MPC

1.8

ClinPred

1.0

GERP RS

5.7

Varity_R

0.98

gMVP

0.67

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