3-30672334-A-G

Variant names:

• chr3-30672334-A-G
• rs193922660
• NM_003242.6:c.1151A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_003242.6(TGFBR2):​c.1151A>G​(p.Asn384Ser) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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:2
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Protein kinase (size 300) in uniprot entity TGFR2_HUMAN there are 34 pathogenic changes around while only 5 benign (87%) in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-30672334-A-G is Pathogenic according to our data. Variant chr3-30672334-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36860.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1151A>G	p.Asn384Ser	missense_variant	Exon 4 of 7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1151A>G	p.Asn384Ser	missense_variant	Exon 4 of 7	1	NM_003242.6	ENSP00000295754.5
TGFBR2	ENST00000359013.4	c.1226A>G	p.Asn409Ser	missense_variant	Exon 5 of 8	1		ENSP00000351905.4
TGFBR2	ENST00000672866.1	n.2747A>G		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1 Uncertain:1

Aug 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N384S variant (also known as c.1151A>G), located in coding exon 4 of the TGFBR2 gene, results from an A to G substitution at nucleotide position 1151. The asparagine at codon 384 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in individuals with concerns for Loeys-Dietz syndrome; however, clinical details were limited in some cases (Loeys BL et al. N Engl J Med, 2006 Aug;355:788-98; Singh KK et al. Hum Mutat, 2006 Aug;27:770-7; Ambry internal data; external communication). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 384 of the TGFBR2 protein (p.Asn384Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 16799921, 16928994; internal data). ClinVar contains an entry for this variant (Variation ID: 36860). 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. -

not specified Pathogenic:1

Oct 02, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TGFBR2 c.1151A>G; p.Asn384Ser variant (rs193922660) has been described in multiple individuals with features of Loeys-Dietz syndrome (Frederic 2009, Loeys 2006, Singh 2006). This variant contains an entry in ClinVar (Variation ID: 36860) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at codon 384 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Moreover, multiple missense variants in neighboring codons also located in the serine-threonine kinase domain have been identified in cohorts of Loeys-Dietz syndrome patients (Stheneur 2008). Based on available information, this variant is considered likely pathogenic. REFERENCES Frederic MY et al. A new locus-specific database (LSDB) for mutations in the TGFBR2 gene: UMD-TGFBR2. Hum Mutat. 2008 Jan;29(1):33-8. Loeys BL et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24;355(8):788-98. Singh KK et al. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat. 2006 Aug;27(8):770-7. Stheneur C et al. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. Hum Mutat. 2008 Nov;29(11):E284-95. -

Loeys-Dietz syndrome Pathogenic:1

Aug 18, 2011

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

not provided Uncertain:1

Aug 13, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as likely pathogenic in 2 patients with the clinical diagnosis of Loeys-Dietz syndrome (SCV000053213.1; ClinVar Variant ID# 36860; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 17061023, 16799921) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.95		Loss of catalytic residue at N384 (P = 0.0047);.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.96

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: rs193922660; hg19: chr3-30713826; COSMIC: COSV55452252;