3-30691478-G-A

Variant names:

• chr3-30691478-G-A
• rs104893815
• NM_003242.6:c.1583G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003242.6(TGFBR2):​c.1583G>A​(p.Arg528His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 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. R528C) 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:6
• Conservation: PhyloP100: 10.0
• Publications: 43 publications found

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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Loeys-Dietz syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P
• Loeys-Dietz syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr3-30691477-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 91 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 2.2437 (below the threshold of 3.09). Trascript score misZ: 2.9378 (below the threshold of 3.09). GenCC associations: The gene is linked to Loeys-Dietz syndrome, familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 3-30691478-G-A is Pathogenic according to our data. Variant chr3-30691478-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1583G>A	p.Arg528His	missense_variant	Exon 7 of 7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1583G>A	p.Arg528His	missense_variant	Exon 7 of 7	1	NM_003242.6	ENSP00000295754.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Dec 05, 2024

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 histidine, which is basic and polar, at codon 528 of the TGFBR2 protein (p.Arg528His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 15731757, 16928994, 19996017, 20956634, 22488992, 23103230, 25116393). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12511). 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%. For these reasons, this variant has been classified as Pathogenic. -

May 21, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R528H pathogenic mutation (also known as c.1583G>A), located in coding exon 7 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1583. The arginine at codon 528 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with Loeys-Dietz syndrome; in at least one individual, it was determined to be de novo (Loeys BL et al. Nat Genet, 2005 Mar;37:275-81; Ting TW et al. Eur J Pediatr, 2014 Mar;173:387-91; Kuppler KM et al. Am J Med Genet A, 2012 May;158A:1212-5). This variant may have an impact on protein function (Inamoto S et al. Cardiovasc Res, 2010 Dec;88:520-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Loeys-Dietz syndrome Pathogenic:1

Aug 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg528His variant in TGFBR2 has been identified in >8 individuals with Loeys -Dietz syndrome and was found to occur de novo in one of these individuals (Loey s 2005, Loeys 2006, LMM unpublished data). It was absent from large population s tudies. In vitro and in vivo functional studies provide evidence that the Arg528 His variant may impact protein function. Computational prediction tools and cons ervation analysis suggest that the Arg528His variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM). -

Loeys-Dietz syndrome 2 Pathogenic:1

Mar 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Nov 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple unrelated patients from different ethnic backgrounds with LoeysDietz syndrome (LDS) either referred for genetic testing at GeneDx or in published literature (PMID: 16928994, 15731757, 17470566, 18781618, 23884466, 23103230); Published functional studies demonstrate variant has a dominant-negative effect on the TGFBR2 gene (PMID: 21267002, 21098638, 20628007); 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: 22488992, 30406707, 15731757, 21098638, 17470566, 18781618, 19996017, 20628007, 23103230, 16791849, 23884466, 27879313, 27508510, 31536524, 32152251, 34916229, 36493725, 21267002, 16928994) -

Colorectal cancer, hereditary nonpolyposis, type 6 Pathogenic:1

Mar 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H;.
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.94		Gain of catalytic residue at R528 (P = 0.0184);.;
MVP		1.0
MPC		1.6
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		0.98
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893815; hg19: chr3-30732970; COSMIC: COSV55442586;