Genetic Variant TGFBR2:p.Arg528Cys (chr3-30691477-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 6.05

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.1582C>T	p.Arg528Cys	missense_variant	Exon 7 of 7	ENST00000295754.10	NP_003233.4	P37173-1A3QNQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10 link	c.1582C>T	p.Arg528Cys	missense_variant	Exon 7 of 7	1	NM_003242.6	ENSP00000295754.5		P37173-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Loeys-Dietz syndrome 2

Pathogenic:3

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Moderate+PS4_Moderate+PP4+PM6_Strong+PM5 -

Sep 26, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:2

Apr 04, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 09, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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‚ÄìDietz 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). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt TGFBR2 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.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

Apr 16, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Loeys-Dietz syndrome

Pathogenic:1

Feb 09, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.2

H;.

PrimateAI

Pathogenic

0.85

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over