3-30688476-C-T

Variant names:

• chr3-30688476-C-T
• rs863223852
• NM_003242.6:c.1489C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_003242.6(TGFBR2):​c.1489C>T​(p.Arg497*) variant causes a stop gained 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFBR2 NM_003242.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.14

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-30688476-C-T is Pathogenic according to our data. Variant chr3-30688476-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 213934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1489C>T	p.Arg497*	stop_gained	Exon 6 of 7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1489C>T	p.Arg497*	stop_gained	Exon 6 of 7	1	NM_003242.6	ENSP00000295754.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Dec 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TGFBR2 protein in which other variant(s) (p.Gln511*) have been determined to be pathogenic (PMID: 15235604, 18781618). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 213934). This variant is also known as p.R522X. This premature translational stop signal has been observed in individual(s) with aortic dilatation and incomplete Marfan syndrome (PMID: 16799921, 18781618, 28225382; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg497*) in the TGFBR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 71 amino acid(s) of the TGFBR2 protein. -

Aug 14, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R497* pathogenic mutation (also known as c.1489C>T) located in coding exon 6 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1489. This changes the amino acid from an arginine to a stop codon within coding exon 6. This stop codon occurs at the 3' terminus of TGFBR2 and is not expected to trigger nonsense-mediated decay. However, this variant eliminates the last 71 amino acids, including 48 amino acids from the C-terminal end of the protein kinase domain. This alteration has been detected in patients from Loeys-Dietz syndrome (LDS), Marfan syndrome-like, and thoracic aortic aneurysm and dissection (TAAD) cohorts in patients reported to have TAAD and other features consistent with LDS (Singh et al. Hum Mutat. 2006;27(8):770-7; Stheneur C et al. Hum Mutat.2008;29(11):E84-95; Jondeau G et al. Circ Cardiovasc Genet. 2016;9(6):548-558; Weerakkody R et al. Genet. Med. 2018 [Epub ahead of print]). In addition, this mutation has been reported to segregate with disease features in families (Cauldwell M et al. Int J Cardiol. 2016;214:491-2; Tooley MJ et al. Clin Dysmorphol. 2017;26(2):91-94). Multiple nonsense and missense alterations in the C-terminal end of the kinase domain have been associated with LDS or related phenotypes (Loeys BL et al. N Engl J Med. 2006;355:788-98; Stheneur C et al. Hum Mutat. 2008;29:E284-95; Horbelt D et al. J Cell Sci. 2010;123:4340-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

-

Centre for Genomic and Experimental Medicine, University of Edinburgh

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Loeys-Dietz syndrome 2 Pathogenic:2

Dec 30, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Loeys-Dietz syndrome Pathogenic:1

May 26, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg497X variant in TGFBR2 has been previously reported in 1 individual with Loeys-Dietz syndrome (LDS) and segregated with disease in at least 6 affected relatives (Tooley 2017). It has also been reported as a de novo occurrence in 1 individual with clinical features of LDS, though it was not clear if maternity and paternity were confirmed (Yang 2012). Additionally, this variant has also been reported in 2 individuals with incomplete Marfan syndrome (Singh et al. 2006, Stheneur et al. 2008). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 213934) and is absent from large population studies. This nonsense variant leads to a premature termination codon at position 497. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing 13% of the coding region, with about 72 amino acids removed. Several truncating variants located downstream of the p.Arg497X variant have been described in individuals with TGFBR2-associated disorders (Stheneur 2008, LMM unpublished data). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LDS. ACMG/AMP criteria applied: PM2, PVS1_strong, PP1_Moderate, PM6. -

not provided Pathogenic:1

Oct 16, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in multiple unrelated individuals with confirmed or suspected Loeys-Dietz syndrome referred for genetic testing at GeneDx and in published literature (PMID: 16799921, 27879313, 28225382, 29543232, 27100340); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 71 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 18781618, 22113417, 25525159, 17061023, 19996017, 28225382, 29543232, 27879313, 16799921, 27100340) -

Connective tissue disorder Pathogenic:1

Jun 01, 2018

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.91
GERP RS		5.4

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: rs863223852; hg19: chr3-30729968; COSMIC: COSV55443474;