chr3-30674228-C-T

Position:

• chr3-30674228-C-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.1378C>T​(p.Arg460Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,838 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. R460H) 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: 4.09

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 chr3-30674229-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 3-30674228-C-T is Pathogenic according to our data. 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. Variant chr3-30674228-C-T is described in Lovd as [Likely_pathogenic]. Variant chr3-30674228-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.1378C>T	p.Arg460Cys	missense_variant	5/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1378C>T	p.Arg460Cys	missense_variant	5/7	1	NM_003242.6	P1
TGFBR2	ENST00000359013.4	c.1453C>T	p.Arg485Cys	missense_variant	6/8	1
TGFBR2	ENST00000672866.1	n.2974C>T		non_coding_transcript_exon_variant	5/7
TGFBR2	ENST00000673203.1	n.256C>T		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2022	Reported in multiple individuals with familial thoracic aortic aneurysm and dissection (TAAD) and in individuals who met diagnostic criteria for Marfan syndrome (Pannu et al., 2005; Singh et al., 2006; Tran-Fadulu et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies and in vitro assays have demonstrated that R460C affects protein trafficking, exhibits a dominant-negative effect, and fails to induce extracellular signal-regulated kinase (ERK) signaling activity (Horbelt et al., 2010).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21267002, 25644172, 19159394, 16251899, 27508510, 16799921, 23685554, 23276923, 28152038, 16027248, 19542084, 21098638) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Loeys-Dietz syndrome 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 26, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 28, 2023	This variant has been reported in multiple individuals with thoracic aortic aneurysm and dissection (TAAD), and it has been reported to co-segregate with TAAD in multiple families (PMID: 16799921, 16027248, 19159394, 19542084). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). It is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 21098638). A different missense substitution at this amino acid residue, p.Arg460His, has been previously reported in individuals with TAAD and Loeys-Dietz syndrome, and it is classified as pathogenic (ClinVar variation ID 12515), which supports the functional importance of this position. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 460 of the TGFBR2 protein (p.Arg460Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR2-related disease (PMID: 16027248, 16799921, 19159394, 19542084). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12514). 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, 16251899, 21267002, 25644172, 27508510; 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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.98		Loss of MoRF binding (P = 0.0864);.;
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
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: rs104893811; hg19: chr3-30715720; COSMIC: COSV55452571;