3-30672246-G-C

Variant names:

• chr3-30672246-G-C
• rs104893813
• NM_003242.6:c.1063G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_003242.6(TGFBR2):​c.1063G>C​(p.Ala355Pro) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A355T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.95
• Publications: 10 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 10 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.982
• PP5: Variant 3-30672246-G-C is Pathogenic according to our data. Variant chr3-30672246-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12509.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003242.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	NM_003242.6	MANE Select	c.1063G>C	p.Ala355Pro	missense	Exon 4 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1246G>C	p.Ala416Pro	missense	Exon 6 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1171G>C	p.Ala391Pro	missense	Exon 5 of 8	NP_001394056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.1063G>C	p.Ala355Pro	missense	Exon 4 of 7	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.1138G>C	p.Ala380Pro	missense	Exon 5 of 8	ENSP00000351905.4
	TGFBR2	ENST00000714391.1		c.1036G>C	p.Ala346Pro	missense	Exon 5 of 8	ENSP00000519658.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jun 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with proline at codon 355 of the TGFBR2 protein (p.Ala355Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 15731757, Invitae). ClinVar contains an entry for this variant (Variation ID: 12509). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Loeys-Dietz syndrome Pathogenic:1

Jun 24, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TGFBR2 c.1063G>C (p.Ala355Pro) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245344 control chromosomes (gnomAD and Loeys_2005). c.1063G>C has been reported in the literature in individuals affected with Loeys-Dietz Syndrome (Loeys_2005). These data indicate that the variant may be associated with disease. One study demonstrated intracellular accumulation of collagen type I in fibroblasts collected from the patient carrying this variant (Barnett_2011). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Loeys-Dietz syndrome 2 Pathogenic:1

Mar 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Colorectal cancer, hereditary nonpolyposis, type 6 Uncertain:1

Dec 10, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.92		Gain of disorder (P = 0.0609)
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.99
gMVP		0.96
Mutation Taster		=6/94	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: rs104893813; hg19: chr3-30713738;