1-218436110-C-T

Position:

• chr1-218436110-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_003238.6(TGFB2):​c.895C>T​(p.Arg299Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,422 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R299Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFB2 NM_003238.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.37

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-218436111-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 381708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85
• PP5: Variant 1-218436110-C-T is Pathogenic according to our data. Variant chr1-218436110-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-218436110-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-218436110-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB2	NM_003238.6	c.895C>T	p.Arg299Trp	missense_variant	5/7	ENST00000366930.9
TGFB2	NM_001135599.4	c.979C>T	p.Arg327Trp	missense_variant	6/8
TGFB2	NR_138148.2	n.2146C>T		non_coding_transcript_exon_variant	5/7
TGFB2	NR_138149.2	n.2230C>T		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB2	ENST00000366930.9	c.895C>T	p.Arg299Trp	missense_variant	5/7	1	NM_003238.6	P1
TGFB2	ENST00000366929.4	c.979C>T	p.Arg327Trp	missense_variant	6/8	1
TGFB2	ENST00000479322.1	n.379C>T		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461422 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726984

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Nov 15, 2019	The c.979C>T variant in the TGFB2 gene results in an amino acid change at residue 327 from an arginine to a tryptophan in the resultant protein (p.Arg327Trp). Also known as c.895C>T (p.Arg299Trp) using an alternate transcript, this variant has been reported in multiple individuals with Loeys-Dietz syndrome and thoracic aortic aneurysms and dissections (PMID: 22772368, 26854089, 23102774). This variant is located in RKKR-motif, an important protein domain where other pathogenic variants have been described. Another variant at this same amino acid position (p.Arg299Gln) has also been reported in association with aortic aneurysms and dissections (PMID: 23102774, 25644172). Multiple lines of in-silico algorithms predict this change to be deleterious. In addition, this variant is absent from population databases (gnomAD). We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 04, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 299 of the TGFB2 protein (p.Arg299Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Loeys-Dietz syndrome and syndromic thoracic aortic aneurysms and dissections (PMID: 22772368, 23102774, 26854089). It has also been observed to segregate with disease in related individuals. This variant is also known as c.979C>T (p.Arg327Trp). ClinVar contains an entry for this variant (Variation ID: 213845). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2022	Not observed in large population cohorts (gnomAD); Located in the RKKR motif, where a significant number of missense variants have been reported in association with LDS to date (Schepers et al., 2018); 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: 22772368, 26854089, 31191903, 33125268, 29907982, 29392890) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -

Familial aortopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 06, 2020

Variant summary: TGFB2 c.895C>T (p.Arg299Trp) results in a non-conservative amino acid change located in the C-terminal domain (IPR001839) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250514 control chromosomes (gnomAD). The variant, c.895C>T (also known asc.979C>T (p.Arg327Trp) in the literature), has been reported in the literature in multiple individuals and families affected with Aortopathy, and has been observed to segregate with the disease in at least two families (e.g. Lindsay_2012, Schubert_2016, Bashari_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely pathogenic (2x) or pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The p.R299W variant (also known as c.895C>T), located in coding exon 5 of the TGFB2 gene, results from a C to T substitution at nucleotide position 895. The arginine at codon 299 is replaced by tryptophan, an amino acid with dissimilar properties. This variant (described as NM_001135599.2:c.979C>T, p.R327W) has been reported in multiple affected individuals with Loeys-Dietz syndrome or syndromic thoracic aortic aneurysm findings; co-segregation was also reported in some affected relatives (Lindsay ME et al. Nat. Genet., 2012 Jul;44:922-7; Renard M et al. Int. J. Cardiol., 2013 May;165:584-7; Schubert JA et al. Am. J. Med. Genet. A, 2016 May;170A:1288-94; Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192; Bashari H et al. SAGE Open Med Case Rep, 2019 May;7:2050313X19852539). A different variant affecting this codon, p.R299Q, c.896G>A (also referred to as p.R327Q, c.980G>A) has been reported in association with syndromic thoracic aortic aneurysm findings (Renard M et al. Int. J. Cardiol., 2013 May;165:584-7; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9). This variant is considered to be rare based on population 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. -

TGFB2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 09, 2022

The TGFB2 c.895C>T variant is predicted to result in the amino acid substitution p.Arg299Trp. This variant, also known as p.Arg327Trp in the literature, was reported in multiple individuals with Loeys-Dietz syndrome presenting thoracic aortic aneurysms and dissections or coronary artery dissections (Lindsay et al. 2012. PubMed ID: 22772368; Schubert et al. 2016. PubMed ID: 26854089; Overwater et al. 2018. PubMed ID: 29907982; Bashari et al. 2019. PubMed ID: 31191903; Carss et al. 2020. PubMed ID: 33125268). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.67		Loss of disorder (P = 0.0182);.;
MVP		0.92
MPC		1.8
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.72
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs863223792; hg19: chr1-218609452;