3-30691504-C-T

Position:

• chr3-30691504-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_003242.6(TGFBR2):​c.1609C>T​(p.Arg537Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.01

Genes affected

TGFBR2 (HGNC:11773): (transforming growth factor beta receptor 2) The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a region_of_interest Sufficient for interaction with CLU (size 128) in uniprot entity TGFR2_HUMAN there are 20 pathogenic changes around while only 1 benign (95%) in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 3-30691504-C-T is Pathogenic according to our data. Variant chr3-30691504-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30691504-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1609C>T	p.Arg537Cys	missense_variant	7/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1609C>T	p.Arg537Cys	missense_variant	7/7	1	NM_003242.6	ENSP00000295754	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	Centre for Genomic and Experimental Medicine, University of Edinburgh	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 2022	The p.R537C pathogenic mutation (also known as c.1609C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1609. The arginine at codon 537 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with thoracic aortic aneurysm and dissection (TAAD) (Mizuguchi T et al. Nat Genet, 2004 Aug;36:855-60; Aalberts JJ et al. Neth Heart J, 2008 Sep;16:299-304; Stheneur C et al. Hum Mutat, 2008 Nov;29:E284-95; Edelman JJ et al. Interact Cardiovasc Thorac Surg, 2011 May;12:863-5; Luo M et al. Clin Chim Acta, 2016 May;456:144-148; Somers AE et al. Am J Med Genet A, 2016 07;170:1786-90; Weerakkody R et al. Genet Med, 2018 11;20:1414-1422; Zheng J et al. Int J Legal Med, 2018 Sep;132:1273-1280; Wang Z et al. Biomed Res Int, 2020 Oct;2020:7857043). Additionally, in vitro assays showed this alteration impacts protein function (Mizuguchi T et al. Nat Genet, 2004 Aug;36:855-60; Horbelt D et al. J Cell Sci, 2010 Dec;123:4340-50). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 537 of the TGFBR2 protein (p.Arg537Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR2-related diseases (PMID: 15235604, 18781618, 18827873, 21324918, 25116393, 27112580). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12507). 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 TGFBR2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGFBR2 function (PMID: 15235604, 20829218, 21098638). For these reasons, this variant has been classified as Pathogenic. -

Loeys-Dietz syndrome 2 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 27, 2022	PS4, PS3, PM5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2004	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in severe impairment of TGF-beta signaling activity (Mizuguchi et al., 2004; Horbelt et al., 2010); 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: 18827873, 26877057, 20628007, 15235604, 21324918, 21098638, 35753512, 30056620, 33083483, 29543232, 35058154, 27112580, 31915033, 18781618) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.89		Gain of glycosylation at S539 (P = 0.0175);.;
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.92

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: rs104893809; hg19: chr3-30732996; COSMIC: COSV55442890;