3-30691477-C-T

Position:

• chr3-30691477-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.1582C>T​(p.Arg528Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R528H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 6.05

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 18 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-30691478-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-30691477-C-T is Pathogenic according to our data. Variant chr3-30691477-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30691477-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1582C>T	p.Arg528Cys	missense_variant	7/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1582C>T	p.Arg528Cys	missense_variant	7/7	1	NM_003242.6	ENSP00000295754.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 26, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS3_Moderate+PS4_Moderate+PP4+PM6_Strong+PM5 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 04, 2016	The p.R528C pathogenic mutation (also known as c.1582C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1582. The arginine at codon 528 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the protein kinase domain. This alteration has been described in several patients with Loeys-Dietz syndrome, and in some cases, the occurrence was reported to be de novo (Loeys BL et al. Nat. Genet. 2005;37(3):275-81). In a study utilizing functional in vitro analyses, this alteration has demonstrated reduced protein expression and TGFβ signaling resulting from a dominant-negative effect (Horbelt D et al. J Cell Sci. 2010;123(Pt 24):4340-50). Based on the available evidence, p.R528C is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 528 of the TGFBR2 protein (p.Arg528Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Loeys–Dietz syndrome (PMID: 15731757, 18781618, 19875893, 20144264). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12512). 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. Experimental studies have shown that this missense change affects TGFBR2 function (PMID: 21098638). This variant disrupts the p.Arg528 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15731757, 18781618, 21098638, 23103230). 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2022	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; Published functional studies demonstrate that this variant results in decreased protein expression and has a dominant-negative effect on TGF-beta induced Smad and ERK signalling (Horbelt et al., 2010); This variant is associated with the following publications: (PMID: 16928994, 23884466, 15731757, 19875893, 18781618, 20144264, 22734312, 34456093, 27535533, 21098638, 17330129, 32352226, 33436942, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 16, 2017	- -

Loeys-Dietz syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 09, 2018

The p.Arg528Cys variant in TGFBR2 has been reported in >5 individuals with Loeys -Dietz syndrome, and occurred de novo in at least 3 of these individuals (Loeys 2005, LeMaire 2007, Stheneur 2008, Frischmeyer-Guerrerio 2013). Additionally, it has also been reported by other clinical laboratories in ClinVar (Variation ID 12512). It was absent from large population studies. In vitro functional studies provide evidence that the p.Arg528Cys variant may impact protein function (Horb elt 2010) and computational prediction tools and conservation analysis suggest t hat the p.Arg528Cys variant may impact the protein. Furthermore, a different pat hogenic variant (p.Arg528His) has been reported in several individuals with Loey s-Dietz syndrome at the same position, supporting this change may not be tolerat ed. In summary, this variant meets criteria to be classified as pathogenic for L oeys-Dietz syndrome in an autosomal dominant manner based upon multiple de novo occurrences, absence from controls, functional and computational evidence and pr esence of another pathogenic variant at the same amino acid position. ACMG/AMP C riteria applied (Richards 2015): PM6_Strong, PM2, PM5, PP3, PS3_Supporting. -

TGFBR2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2024

The TGFBR2 c.1582C>T variant is predicted to result in the amino acid substitution p.Arg528Cys. This variant was detected in multiple individuals with Loeys-Dietz syndrome, including at least 2 de novo occurrences (Loeys et al. 2005. PubMed ID: 15731757, Frischmeyer-Guerrerio et al. 2013. PubMed ID: 23884466, Horbelt et al. 2010. PubMed ID: 21098638, LeMaire et al. 2007. PubMed ID: 17330129; Stheneur et al. 2008. PubMed ID: 18781618, Mariucci et al. 2020. PubMed ID: 32352226). Functional studies suggest this variant affects protein function (Horbelt et al. 2010. PubMed ID: 21098638). Different missense variants affecting this amino acid have been reported in patient with Loeys-Dietz syndrome (p.Arg528His, p.Arg528Pro, Loeys et al. 2005. PubMed ID: 15731757, Almpani et al. 2022. PubMed ID: 34916229, Carmignac et al. 2012. PubMed ID: 23103230, Akazawa et al. 2015. PubMed ID: 26096872). The c.1582C>T variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.94		Gain of catalytic residue at L529 (P = 0.0126);.;
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
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: rs104893810; hg19: chr3-30732969; COSMIC: COSV55443375;