rs113605875

chr9-99149253-G-Achr9-99149253-G-Cchr9-99149253-G-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.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. R487P) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 10.0

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain 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 ClinVar as [Likely_pathogenic]. Clinvar id is 12526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TGFBR1
• 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	UniProt
TGFBR1	NM_004612.4	c.1460G>A	p.Arg487Gln	missense_variant	9/9	ENST00000374994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR1	ENST00000374994.9	c.1460G>A	p.Arg487Gln	missense_variant	9/9	1	NM_004612.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152028 Hom.: 0 Cov.: 32

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.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152028 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74252

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

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. -
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	Invitae	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. -

Loeys-Dietz syndrome 1 Pathogenic:3

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 -
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	- -

not provided Pathogenic:2

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) -
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 -

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. -

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	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
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	D
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

Other links and lift over

dbSNP: rs113605875; hg19: chr9-101911535; COSMIC: COSV66625173; COSMIC: COSV66625173;