rs886039551

chr3-30674186-G-Achr3-30674186-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003242.6(TGFBR2):c.1336G>A(p.Asp446Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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. D446E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0

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 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-30674188-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213932.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-30674186-G-A is Pathogenic according to our data. Variant chr3-30674186-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30674186-G-A is described in Lovd as [Pathogenic]. Variant chr3-30674186-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.1336G>A	p.Asp446Asn	missense_variant	5/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1336G>A	p.Asp446Asn	missense_variant	5/7	1	NM_003242.6	P1
TGFBR2	ENST00000359013.4	c.1411G>A	p.Asp471Asn	missense_variant	6/8	1
TGFBR2	ENST00000672866.1	n.2932G>A		non_coding_transcript_exon_variant	5/7
TGFBR2	ENST00000673203.1	n.214G>A		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 24, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 446 of the TGFBR2 protein (p.Asp446Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with aortic dilation or Loeys-Dietz syndrome (PMID: 16251899, 18781618, 19006214, 21484991, 22095581, 22259224, 23884466, 24792536). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265447). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt TGFBR2 function. This variant disrupts the p.Asp446 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (PMID: 21484991), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2017	The p.D446N pathogenic mutation (also known as c.1336G>A), located in coding exon 5 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1336. The aspartic acid at codon 446 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been detected in multiple unrelated individuals with Loeys-Dietz syndrome (LDS), reported as occurring de novo in a few cases, and described to segregate with disease in a few families (Disabella E et al. Eur. J. Hum. Genet., 2006 Jan;14:34-8; Stheneur C et al. Hum. Mutat., 2008 Nov;29:E284-95; Watanabe Y et al. Am. J. Med. Genet. A, 2008 Dec;146A:3070-4; Sousa SB et al. Am. J. Med. Genet. A, 2011 May;155A:1178-83; Ben Amor IM et al. J. Bone Miner. Res., 2012 Mar;27:713-8; Frischmeyer-Guerrerio PA et al. Sci Transl Med, 2013 Jul;5:195ra94; Longmuir SQ et al. J AAPOS, 2014 Jun;18:288-90). Internal structural analysis suggested that this alteration would destabilize the structure of the C-terminal lobe of the kinase domain. 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	Revvity Omics, Revvity	Aug 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2023	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: 23884466, 18781618, 22095581, 16835936, 16251899, 22259224, 32352226, 24792536, 32152251, 19006214, 30219046) -

Loeys-Dietz syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Sep 30, 2016

- -

Loeys-Dietz syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Centre of Medical Genetics, University of Antwerp

Mar 01, 2021

PM2, PS1, PM1, PP1 -

TGFBR2-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2022

The TGFBR2 c.1336G>A variant is predicted to result in the amino acid substitution p.Asp446Asn. This is a recurrent de novo variant that has been reported in multiple individuals with Loeys-Dietz syndrome (Ben Amor et al. 2012. PubMed ID: 22095581; Jani et al. 2020. PubMed ID: 32152251; Stheneur et al. 2008. PubMed ID: 18781618). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.96		Gain of glycosylation at Y448 (P = 0.0037);.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.99

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: rs886039551; hg19: chr3-30715678; COSMIC: COSV55445539;