1-218436119-C-T

Position:

• chr1-218436119-C-T

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.904C>T​(p.Arg302Cys) variant causes a missense change involving the alteration of a non-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. R302H) 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:6 O:1
• Conservation: PhyloP100: 2.82

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 chr1-218436120-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822
• PP5: Variant 1-218436119-C-T is Pathogenic according to our data. 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. Variant chr1-218436119-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.904C>T	p.Arg302Cys	missense_variant	5/7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.988C>T	p.Arg330Cys	missense_variant	6/8		NP_001129071.1
TGFB2	NR_138148.2	n.2155C>T		non_coding_transcript_exon_variant	5/7
TGFB2	NR_138149.2	n.2239C>T		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.904C>T	p.Arg302Cys	missense_variant	5/7	1	NM_003238.6	ENSP00000355897	P1
TGFB2	ENST00000366929.4	c.988C>T	p.Arg330Cys	missense_variant	6/8	1		ENSP00000355896
TGFB2	ENST00000479322.1	n.388C>T		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:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 302 of the TGFB2 protein (p.Arg302Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Loeys-Dietz syndrome and a syndromic thoracic aortic disorder (PMID: 22772368, 25644172). In at least one individual the variant was observed to be de novo. This variant is also known as c.988C>T, p.Arg330Cys. ClinVar contains an entry for this variant (Variation ID: 224872). 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. This variant disrupts the p.Arg302 amino acid residue in TGFB2. Other variant(s) that disrupt this residue have been observed in individuals with TGFB2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 28, 2018	The TGFB2 c.904C>T; p.Arg302Cys variant (rs869312903), also known as p.Arg330Cys, is reported in the literature in several individuals with symptoms of Loeys-Dietz syndrome or another thoracic aortic disorder (Campens 2015, Lindsay 2012). In one affected individual, this variant was not observed in either parent, suggested a de novo origin (Lindsay 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 302 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at the same codon (p.Arg302Pro) and other variants nearby (p.Arg299Gln and p.Arg299Trp) have been reported in individuals with symptoms of Loeys-Dietz syndrome and are considered to be pathogenic (Campens 2015, Lindsay 2012, Trujillano 2017). Based on available information, the p.Arg302Cys variant is considered to be likely pathogenic. References: Campens L et al. Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. Orphanet J Rare Dis. 2015 Feb 3;10:9. Lindsay ME et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012 Jul 8;44(8):922-7. Trujillano D et al. Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Eur J Hum Genet. 2017 Feb;25(2):176-182. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2020

The p.R302C pathogenic mutation (also known as c.904C>T, or as R330C), located in coding exon 5 of the TGFB2 gene, results from a C to T substitution at nucleotide position 904. The arginine at codon 302 is replaced by cysteine, an amino acid with highly dissimilar 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 alteration has been described in individuals with syndromic thoracic aortic aneurysm and was reported to have occurred de novo in one case (Lindsay ME et al. Nat. Genet., 2012 Aug;44:922-7; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Schepers D et al. Hum. Mutat., 2018 05;39:621-634). Furthermore, a likely pathogenic alteration at the same amino acid position, R302H (also known as R330H), has also been described in individuals with syndromic thoracic aortic disease (Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Loeys-Dietz syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 24, 2020

The p.Arg330Cys variant in TGFB2 has been identified in 4 individuals with clinical features of Loeys-Dietz syndrome and, for one individual, it was absent in both parents suggesting de novo inheritance (Campens 2015 PMID: 25644172; Lindsay 2012 PMID: 22772368; Schepers 2018 PMID: 29392890). In addition, this variant segregated with clinical features of Loeys-Dietz syndrome across 4 relatives with classic and mild features (Russo 2018 PMID: 29742657). This variant is listed in ClinVar (allele ID: 226714) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Loeys Dietz syndrome. ACMG/AMP codes: PM2; PP3; PS4_Moderate; PM6; PP1. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2022

Reported in multiple individuals with syndromic TAAD; also referred to as R330C due to alternate nomenclature (Lindsay et al., 2012; Campens et al., 2015; Russo et al., 2018; Braverman et al., 2020); 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: 25504618, 25163805, 29392890, 25644172, 22772368, 32462795, 29742657) -

Aortic aneurysm, familial thoracic, TGFB2 related Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Likely pathogenic and reported on 12-01-2015 by Lab or GTR ID 26957. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.55		Loss of MoRF binding (P = 0.0021);.;
MVP		0.95
MPC		2.1
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.57
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs869312903; hg19: chr1-218609461;