rs1553303213

Positions:

• chr1-218436120-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The ENST00000366930.9(TGFB2):​c.905G>A​(p.Arg302His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R302C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFB2 ENST00000366930.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.55

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 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000366930.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-218436119-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807
• PP5: Variant 1-218436120-G-A is Pathogenic according to our data. Variant chr1-218436120-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 440982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-218436120-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-218436120-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.905G>A	p.Arg302His	missense_variant	5/7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.989G>A	p.Arg330His	missense_variant	6/8		NP_001129071.1
TGFB2	NR_138148.2	n.2156G>A		non_coding_transcript_exon_variant	5/7
TGFB2	NR_138149.2	n.2240G>A		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.905G>A	p.Arg302His	missense_variant	5/7	1	NM_003238.6	ENSP00000355897	P1
TGFB2	ENST00000366929.4	c.989G>A	p.Arg330His	missense_variant	6/8	1		ENSP00000355896
TGFB2	ENST00000479322.1	n.389G>A		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 4 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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: 0.59; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000440982). Different missense changes at the same codon (p.Arg302Cys, p.Arg302Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000224872, VCV000239515). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 05, 2022	This variant disrupts the p.Arg302 amino acid residue in TGFB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22772368, 25644172). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 440982). This variant is also known as p.Arg330His. This missense change has been observed in individuals with TGFB2-related conditions (PMID: 29907982, 31915033). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 302 of the TGFB2 protein (p.Arg302His). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 25, 2023	PM1, PM2, PM5, PP3, PP5 -

not provided Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2023	Not observed 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: 32307099, 31915033, 29392890, 34916229, 29907982) -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2022

The p.R302H variant (also known as c.905G>A), located in coding exon 5 of the TGFB2 gene, results from a G to A substitution at nucleotide position 905. The arginine at codon 302 is replaced by histidine, an amino acid with highly similar properties. This arginine residue lies in a putative furin cleavage site where precursor TGFβ2 may be cleaved into latency-associated peptide and mature TGFβ2; however, experimental evidence of a cleavage impact is unavailable (Marquardt H et al. J. Biol. Chem., 1987 Sep;262:12127-31). This variant has been described in individuals with syndromic thoracic aortic disease and segregates with disease in one family tested at our laboratory (Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192; Yang H et al. Orphanet J Rare Dis, 2020 01;15:6; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.51		Loss of MoRF binding (P = 0.0082);.;
MVP		0.93
MPC		2.0
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.56
gMVP		0.81

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: rs1553303213; hg19: chr1-218609462;