rs104893816

Positions:

• chr3-30674229-G-A
• chr3-30674229-G-C
• chr3-30674229-G-T

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.1379G>A​(p.Arg460His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R460C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr3-30674228-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 3-30674229-G-A is Pathogenic according to our data. Variant chr3-30674229-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.1379G>A	p.Arg460His	missense_variant	5/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1379G>A	p.Arg460His	missense_variant	5/7	1	NM_003242.6	P1
TGFBR2	ENST00000359013.4	c.1454G>A	p.Arg485His	missense_variant	6/8	1
TGFBR2	ENST00000672866.1	n.2975G>A		non_coding_transcript_exon_variant	5/7
TGFBR2	ENST00000673203.1	n.257G>A		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251464 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727226

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 30, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 460 of the TGFBR2 protein (p.Arg460His). This variant is present in population databases (rs104893816, gnomAD 0.004%). This missense change has been observed in individuals with TGFBR2-related conditions (PMID: 16027248, 16885183, 18852674, 23884466, 25644172, 27508510). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12515). 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: 21098638). This variant disrupts the p.Arg460 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16027248, 16799921, 19542084, 21098638, 21267002; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 03, 2023	The p.R460H variant (also known as c.1379G>A), located in coding exon 5 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1379. The arginine at codon 460 is replaced by histidine, an amino acid with highly similar properties. This variant has been found to segregate in multiple multigenerational families with syndromic and non-syndromic thoracic aortic aneurysm and dissection (TAAD) (Michaowska A et al. Pol Arch Internal Med, 2020 May; Pannu H et al. Circulation, 2005 Jul;112:513-20; Law C et al. J. Med. Genet., 2006 Dec;43:908-16). It has also been reported in several individuals with TAAD (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98; Jawaid Y et al. Case Rep Cardiol, 2018 Dec;2018:8014820; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Disabella E et al. Eur. J. Hum. Genet., 2006 Jan;14:34-8). Experimental studies indicate that this alteration affects TGFBR2 protein internalization and decreases TGFBR2 expression and signaling activity (Horbelt D et al. J. Cell. Sci., 2010 Dec;123:4340-50; Inamoto S et al. Cardiovasc. Res., 2010 Dec;88:520-9). 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. -

Loeys-Dietz syndrome 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 17, 2019	The c.1454G>A (p.Arg485His) variant in the TGFBR2 gene has been reported in multiple unrelated families affected with Thoracic Aortic Aneurysm and Dissection (PMID 16027248,16251899, 16885183, 25644172) and segregates with disease in some of the families (PMID 16027248, 16885183). In vitro analysis showed this variant results in severely compromised internalization of the TGF-beta RII protein (PMID 21098638). Multiple in silico algorithms predicted this p.Arg485His change to be deleterious. Therefore, this c.1454G>A (p.Arg485His) variant in the TGFBR2 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jun 05, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2017

The R460H mutation in the TGFBR2 gene has been reported multiple times in association with Marfan syndrome, TAAD, and related disorders (Pannu H et al., 2005; Disabella E et al., 2006; Law C et al., 2006). Pannu et al. identified R460H in two unrelated families and found this mutation co-segregated with a TAAD phenotype with reduced penetrance. Disabella et al. reported R460H in a 24 year-old female with aortic root dilation who met Ghent criteria for Marfan syndrome. She had a family history of sudden death in her father and paternal aunt (ages 37 and 45, respectively) due to aortic root dissection. Law et al. observed the R460H mutation in one large family with TAAD and a family history of sudden death. Postmortem autopsy on six individuals in this family identified ruptured aortic aneurysm and dissection as the cause of death. Furthermore, R460H was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations at this residue (R460C, R460L) and in nearby residues (M457K, C461Y) have been reported in association with TAAD and other related disorders, supporting the functional importance of this residue and this region of the protein. Moreover, Pannu et al., suggests the R460 residue to be a mutation hot spot" for familial TAAD. Functional studies reported R460H exhibits a dominant-negative effect on extracellular signal-regulated kinase (ERK) and SMAD signaling which leads to a defect in TGF-B signaling (Horbelt D et al., 2010). In summary, R460H in the TGFBR2 gene is interpreted as a disease-causing mutation." -

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	0.87
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.97		Loss of MoRF binding (P = 0.103);.;
MVP		1.0
MPC		1.6
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.97

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: rs104893816; hg19: chr3-30715721; COSMIC: COSV55447151;