NM_003242.6:c.1159G>T

Variant names:

• chr3-30672342-G-T
• rs35766612
• NM_003242.6:c.1159G>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_003242.6(TGFBR2):​c.1159G>T​(p.Val387Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,613,646 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. V387M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 8.05

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]

ACMG classification

Verdict is Benign. 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.08301011).
• BP6: Variant 3-30672342-G-T is Benign according to our data. Variant chr3-30672342-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36862.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=3, Likely_benign=4}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000355 (54/152170) while in subpopulation NFE AF= 0.000514 (35/68030). AF 95% confidence interval is 0.000379. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1159G>T	p.Val387Leu	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.1159G>T	p.Val387Leu	missense_variant	Exon 4 of 7	1	NM_003242.6	ENSP00000295754.5
TGFBR2	ENST00000359013.4	c.1234G>T	p.Val412Leu	missense_variant	Exon 5 of 8	1		ENSP00000351905.4
TGFBR2	ENST00000672866.1	n.2755G>T		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000351 AC: 88 AN: 250480 Hom.: 1 AF XY: 0.000377 AC XY: 51 AN XY: 135314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00261

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000655

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000354 AC: 517 AN: 1461476 Hom.: 1 Cov.: 34 AF XY: 0.000399 AC XY: 290 AN XY: 727044

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00303

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 21 AN XY: 74330

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.0000767 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:4

Sep 19, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Aug 20, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Sep 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18781618, 16791849, 17061023, 24793577) -

May 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TGFBR2 c.1159G>T; p.Val387Leu variant (rs35766612, ClinVar Variation ID: 36862) is reported in the literature in individuals affected with Marfan syndrome, Loeys-Dietz syndrome and related disorders (Lerner-Ellis 2014, Matyas 2006, Stheneur 2008, Wang 2022). It was also found in individuals with arteriovenous malformations (Jensson 2023, Scimone 2020). This variant is found in the Ashkenazi Jewish population with an allele frequency of 0.27% (28/10268 alleles) in the Genome Aggregation Database (v2.1.1). Additionally, another variant at this codon (c.1159G>A; p.Val387Met) has been reported in an individual with Loyes-Dietz syndrome, who also carried a pathogenic TGFBR2 mutation (Loeys 2006), as well as an individual with a clinical diagnosis of Marfan syndrome, who also carried a pathogenic variant in FBN1 (Van der Kolk, 2009); the Val387Met variant is considered likely benign. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.536). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Jensson BO et al. Actionable Genotypes and Their Association with Life Span in Iceland. N Engl J Med. 2023 Nov 9;389(19):1741-1752. PMID: 37937776. Lerner-Ellis JP et al. The spectrum of FBN1, TGFBR1, TGFBR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). Mol Genet Metab. 2014 Jun;112(2):171-6. PMID: 24793577. 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. PMID: 16928994. Matyas G et al. Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. Hum Mutat. 2006 Aug;27(8):760-9. PMID: 16791849. Scimone C et al. Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis. Int J Mol Sci. 2020 Jun 17;21(12):4321. PMID: 32560555. 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. PMID: 18781618. Van der Kolk et al. Marfan syndrome with extreme cardiovascular complications in a patient with mutations in both FBN1 and TGFBR2. Abstract presented at European Human Genetics Conference 2009. May 23 – May 26, 2009; Vienna, Austria. Wang Y et al. Burden of Rare Genetic Variants in Spontaneous Coronary Artery Dissection With High-risk Features. JAMA Cardiol. 2022 Oct 1;7(10):1045-1055. PMID: 36103205. -

not specified Benign:2

Jul 27, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TGFBR2 c.1159G>T (p.Val387Leu) results in a conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 250480 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 112-fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR2 causing Loeys-Dietz Syndrome phenotype (3.1e-06), strongly suggesting that the variant is benign. p.Val387Leu has been reported in the literature in individuals affected with Marfan Syndrome (MFS), Loeys-Dietz Syndrome (LDS) or Thoracic Aortic Aneurysms and Dissections (TAAD) (Matyas_2006, Stheneur_2008, Lerner-Ellis_2014), while it was also reported in a case of Brain arteriovenous malformation (Scimone_2020). Two of these studies reported the variant as likely benign or polymorphism. These reports do not provide unequivocal conclusions about association of the variant with Loeys-Dietz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Aug 20, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome Uncertain:1

Sep 28, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome Uncertain:1

Feb 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vascular dilatation;C0856747:Ascending tubular aorta aneurysm Uncertain:1

May 27, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TGFBR2-related disorder Benign:1

Apr 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.083	T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.47	N;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.89	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.82	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.94	P;.
Vest4		0.49
MutPred		0.73		Loss of methylation at K388 (P = 0.0335);.;
MVP		0.92
MPC		1.3
ClinPred		0.14	T
GERP RS		4.2
Varity_R		0.38
gMVP		0.75

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: rs35766612; hg19: chr3-30713834; COSMIC: COSV55452433;