3-30691486-G-A

Position:

• chr3-30691486-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_003242.6(TGFBR2):​c.1591G>A​(p.Ala531Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,858 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A531D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• 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 11 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, 9 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 chr3-30691487-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3235255.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 3-30691486-G-A is Pathogenic according to our data. Variant chr3-30691486-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165399.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.1591G>A	p.Ala531Thr	missense_variant	7/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1591G>A	p.Ala531Thr	missense_variant	7/7	1	NM_003242.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 25, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 165399). This missense change has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 24793577). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 531 of the TGFBR2 protein (p.Ala531Thr). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 08, 2023	This missense variant replaces alanine with threonine at codon 531 of the TGFBR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with thoracic aortic aneurysm and aortic dissection (TAAD) and segregated with TAAD and/or features of Loeys-Dietz syndrome in 5 affected relatives including two obligate carriers (ClinVar submission ID: SCV000200581.5). This variant has also been reported in an additional unrelated individual with Loeys-Dietz syndrome (PMID: 32887874) and in an individual suspected of having TAAD, Loeys-Dietz syndrome or Marfan syndrome (PMID: 24793577). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 02, 2023	The p.A531T variant (also known as c.1591G>A), located in coding exon 7 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1591. The alanine at codon 531 is replaced by threonine, an amino acid with similar properties, and is located in the kinase domain. This variant has been detected in a cohort suspected of having Marfan syndrome, Loeys-Dietz syndrome (LDS) or thoracic aortic aneurysm and dissection (TAAD), and segregated with TAAD and/or features of LDS in several members of one family (Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6; external lab pers. comm.). This variant has also been detected in additional individuals with TAAD (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Tebben AJ et al. Acta Crystallogr D Struct Biol. 2016 05;72(Pt 5):658-74). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Loeys-Dietz syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 05, 2024

The c.1591G>A (p.Ala531Thr) variant in the TGFBR2 gene that encodes for transforming growth factor beta receptor 2, has been identified in individuals affected with TGFR2-related conditions including thoracic aortic aneurysm and dissection (TAAD), spontaneous coronary artery dissection, aneurysm and Loeys-Dietz syndrome (PMID: 24793577, 32887874, 36103205) and segregated with familial TAAD and/or features of Loeys-Dietz syndrome (ClinVar [ID: 165399, Accession: SCV000200581]). In-silico computational prediction tools suggest that the p.Ala531Thr variant may have deleterious effect on the protein function (REVEL score: 0.837).This variant is found to be absent in the general population database, gnomAD. ClinVar has an entry for this variant (ID: 165399). Therefore, the c.1591G>A (p.Ala531Thr) variant in the TGFBR2 gene is classified as likely pathogenic. -

TGFBR2-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2023

The TGFBR2 c.1591G>A variant is predicted to result in the amino acid substitution p.Ala531Thr. This variant was reported in two patients with Loeys-Dietz syndrome (Table S1, Lerner-Ellis. 2014. PubMed ID: 24793577; Saw. 2020. PubMed ID: 32887874). This variant is listed in ClinVar as uncertain and likely pathogenic, and was reported to segregate with TAAD and/or Loeys-Dietz syndrome in six family members undergoing testing in a different laboratory (https://www.ncbi.nlm.nih.gov/clinvar/variation/165399/). This variant is interpreted as likely pathogenic. -

Loeys-Dietz syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 19, 2014

The Ala531Thr variant in TGFBR2 has been identified by our laboratory in 1 white individual with familial thoracic aortic aneurysm and dissection (familial TAAD ) and segregated with familial TAAD and/or features of Loeys Dietz syndrome in 5 affected relatives including two obligate carriers. It was absent from large po pulation studies. Computational prediction tools and conservation analysis sugge st that the Ala531Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although addition al studies are required to fully establish its clinical significance, the Ala531 Thr variant is classified as likely pathogenic based on the segregation data. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 27, 2022

Identified in an individual with suspected Loeys-Dietz syndrome and in an individual with spontaneous coronary artery dissection, however segregation and detailed clinical information were not provided in either case (Lerner-Ellis et al., 2014; Saw et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32887874, 24793577) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.84		Gain of glycosylation at T530 (P = 0.0201);.;
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.86

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: rs727503477; hg19: chr3-30732978;