1-218436111-G-A

Position:

• chr1-218436111-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_003238.6(TGFB2):​c.896G>A​(p.Arg299Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,496 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. R299W) 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:11
• 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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-218436110-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• PP5: Variant 1-218436111-G-A is Pathogenic according to our data. 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. Variant chr1-218436111-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-218436111-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB2	NM_003238.6	c.896G>A	p.Arg299Gln	missense_variant	5/7	ENST00000366930.9
TGFB2	NM_001135599.4	c.980G>A	p.Arg327Gln	missense_variant	6/8
TGFB2	NR_138148.2	n.2147G>A		non_coding_transcript_exon_variant	5/7
TGFB2	NR_138149.2	n.2231G>A		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB2	ENST00000366930.9	c.896G>A	p.Arg299Gln	missense_variant	5/7	1	NM_003238.6	P1
TGFB2	ENST00000366929.4	c.980G>A	p.Arg327Gln	missense_variant	6/8	1
TGFB2	ENST00000479322.1	n.380G>A		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461496 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727034

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 4 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 07, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg299 amino acid residue in TGFB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22772368, 23102774, 26854089). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt TGFB2 protein function. ClinVar contains an entry for this variant (Variation ID: 381708). This missense change has been observed in individuals with TGFB2-related conditions (PMID: 23102774, 25644172, 29392890, 29510914; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 299 of the TGFB2 protein (p.Arg299Gln). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Loeys-Dietz syndrome (MIM #4614816). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RKKR motif in the latency-associated peptide domain (PMID: 29392890, UniProt). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg299Trp) variant has been classified as both pathogenic and likely pathogenic by diagnostic laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple patients with aortic aneurysms and/or features of a connective tissue disorder (PMIDs: 23102774, 25644172, 29510914, ClinVar). Additionally, this variant has been reported as de novo in one patient (Decipher). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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: 0.57; 3Cnet: 0.91). The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID:VCV000381708/PMID:23102774). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25644172, 29392890, 29510914). A different missense change at the the same codon (p.Arg299Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000213845 / PMID: 22772368). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2024	Identified in patients with TAAD and additional clinical features of Loeys-Dietz syndrome (LDS) referred for genetic testing at GeneDx and in published literature (PMID: 23102774, 25644172, 29510914); 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: 25163805, 25644172, 31785789, 29510914, 29392890, 23102774, 35982159, 33057194) -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 04, 2021	The p.R299Q variant (also known as c.896G>A), located in coding exon 5 of the TGFB2 gene, results from a G to A substitution at nucleotide position 896. The arginine at codon 299 is replaced by glutamine, an amino acid with highly similar properties. This variant (described as NM_001135599.2 c.980G>A p.R327Q) has been reported in individuals with syndromic thoracic aortic aneurysm findings and in a Loeys-Dietz syndrome cohort with limited clinical details (Renard M et al. Int. J. Cardiol., 2013 May;165:584-7; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Schepers D et al. Hum Mutat, 2018 05;39:621-634; Hicks KL et al. J Vasc Surg, 2018 09;68:701-711). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (van de Ven WJ et al. Mol. Biol. Rep., 1990 Nov;14:265-75;Van de Ven WJ et al. Enzyme, 1991;45:257-70; Molloy SS et al. J. Biol. Chem., 1992 Aug;267:16396-402; Dubois CM et al. J. Biol. Chem., 1995 May;270:10618-24; Nakayama K. Biochem. J., 1997 Nov;327 ( Pt 3):625-35; Khalil N. Microbes Infect., 1999 Dec;1:1255-63; Schepers D et al. Hum. Mutat., 2018 05;39:621-634). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 05, 2018	- -

Loeys-Dietz syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 22, 2024

Variant summary: TGFB2 c.896G>A (p.Arg299Gln) results in a conservative amino acid change located in the Transforming growth factor-beta, C-terminal domain (IPR001839) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250514 control chromosomes (gnomAD). c.896G>A has been reported in the literature in multiple individuals affected with features of Loeys-Dietz Syndrome (e.g. Renard_2013, Hicks_2018, Schepers_2018). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.895C>T, p.Arg299Trp), supporting the critical relevance of codon 299 to TGFB2 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 23102774, 31785789, 29510914, 29392890). ClinVar contains an entry for this variant (Variation ID: 381708). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.57
Sift	Benign	0.043	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.62		Loss of MoRF binding (P = 0.0468);.;
MVP		0.94
MPC		1.9
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.58
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1057521150; hg19: chr1-218609453; COSMIC: COSV65108222; COSMIC: COSV65108222;