chr3-30688395-T-G

Position:

• chr3-30688395-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_003242.6(TGFBR2):​c.1408T>G​(p.Tyr470Asp) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91

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]

TGFBR2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 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, 0.939
• PP5: Variant 3-30688395-T-G is Pathogenic according to our data. Variant chr3-30688395-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1408T>G	p.Tyr470Asp	missense_variant	6/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1408T>G	p.Tyr470Asp	missense_variant	6/7	1	NM_003242.6	ENSP00000295754.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

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	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr470 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26848186, 27879313; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 217016). This missense change has been observed in individuals with clinical features of Loeys-Dietz syndrome (PMID: 25326637; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 470 of the TGFBR2 protein (p.Tyr470Asp). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 03, 2020	The p.Y470D pathogenic mutation (also known as c.1408T>G), located in coding exon 6 of the TGFBR2 gene, results from a T to G substitution at nucleotide position 1408. The tyrosine at codon 470 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant has been previously reported in an individual with suspected Marfan or Loeys-Dietz syndrome (Lee H et al. JAMA 2014 Nov; 312(18):1880-7) and segregates with disease in one family tested in our laboratory (Ambry internal data). In a study of patients with aortic aneurysms/dissections, an alteration of the same codon, p.Y470S (c.1409A>C), in the protein kinase domain was detected in one patient (Waldmüller S et al. Eur J Cardiothorac Surg. 2007;31(6):970-5). Phosphorylation of p.Y470 has been shown to be important for TGFBR2 function (Chen X et al. J. Clin. Invest. 2014 Aug; 124(8):3295-310), and TGFBR2 is inactivated in a cancer cell line with p.Y470D as well as a second TGFBR2 substitution (p.K52T; Grady WM et al. Cancer Res. 1999 Jan; 59(2):320-4). Based on the supporting evidence, p.Y470D is interpreted as a disease-causing mutation. -

Loeys-Dietz syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Apr 30, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-9.2	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.75		Gain of glycosylation at Y470 (P = 0.0112);.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs863224935; hg19: chr3-30729887; COSMIC: COSV55452852;