rs1553303352

Positions:

• chr1-218437368-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_003238.6(TGFB2):​c.958C>T​(p.Arg320Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R320H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TGFB2 NM_003238.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.91

Genes affected

TGFB2 (HGNC:11768): (transforming growth factor beta 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a chain Transforming growth factor beta-2 (size 111) in uniprot entity TGFB2_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_003238.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 1-218437368-C-T is Pathogenic according to our data. Variant chr1-218437368-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-218437368-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB2	NM_003238.6	c.958C>T	p.Arg320Cys	missense_variant	6/7	ENST00000366930.9
TGFB2	NM_001135599.4	c.1042C>T	p.Arg348Cys	missense_variant	7/8
TGFB2	NR_138148.2	n.2209C>T		non_coding_transcript_exon_variant	6/7
TGFB2	NR_138149.2	n.2293C>T		non_coding_transcript_exon_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB2	ENST00000366930.9	c.958C>T	p.Arg320Cys	missense_variant	6/7	1	NM_003238.6	P1
TGFB2	ENST00000366929.4	c.1042C>T	p.Arg348Cys	missense_variant	7/8	1
TGFB2	ENST00000479322.1	n.442C>T		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454378 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 723334

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 03, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 320 of the TGFB2 protein (p.Arg320Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TGFB2-related conditions (PMID: 25046559, 27782106; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495213). 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 TGFB2 protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 28, 2019	The TGFB2 c.958C>T; p.Arg320Cys variant (rs1553303352), also known as p.Arg348Cys using alternative nomenclature, is reported in the literature in multiple individuals affected with aortic aneurysm or dissection (Al Maskari 2016, Gago-Diaz 2014). This variant was observed to cosegregate with disease in multiple affected individuals in at least two families, although its detection in some unaffected relatives suggests it may exhibit incomplete penetrance (Al Maskari 2016, Gago-Diaz 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported in ClinVar (Variation ID: 495213). The arginine at codon 320 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, immunoblotting and immunofluorescence of aortic tissue from an affected individual with this variant exhibited substantially increased levels of TGFB1 and TGFB2 protein compared to unaffected controls (Al Maskari 2016). An increase in TGFB2 in affected aortic tissue may be an indirect effect of haploinsufficiency in aortic disease (Boileau 2012). Based on available information, this variant is considered to be likely pathogenic. References: Al Maskari R et al. A missense TGFB2 variant p.(Arg320Cys) causes a paradoxical and striking increase in aortic TGFB1/2 expression. Eur J Hum Genet. 2016 Jan;25(1):157-160. Boileau C et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 2012 Jul 8;44(8):916-21. Gago-Diaz M et al. Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease. Clin Chim Acta. 2014 Nov 1;437:88-92. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 06, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000495213 / PMID: 25046559). A different missense change at the same codon (p.Arg320His) has been reported to be associated with TGFB2 related disorder (PMID: 33418956). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 23, 2022

Reported in two unrelated individuals with non-syndromic aortic disease and Loeys-Dietz syndrome type 4 (LDS4) (also reported as p.(R348C) due to alternate nomenclature), and segregates with disease in affected family members from these two families (Gago-Diaz et al., 2014; Al Maskari et al., 2016); 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; This variant is associated with the following publications: (PMID: 25046559, 27782106) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.5	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.84		Gain of sheet (P = 0.1208);.;
MVP		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553303352; hg19: chr1-218610710;