rs1553303352

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_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

Scores

17
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.91
Variant links:
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]

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ACMG classification

Classification made for transcript

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 Protein UniProt
TGFB2NM_003238.6 linkuse as main transcriptc.958C>T p.Arg320Cys missense_variant 6/7 ENST00000366930.9 NP_003229.1 P61812-1Q59EG9
TGFB2NM_001135599.4 linkuse as main transcriptc.1042C>T p.Arg348Cys missense_variant 7/8 NP_001129071.1 P61812-2Q59EG9
TGFB2NR_138148.2 linkuse as main transcriptn.2209C>T non_coding_transcript_exon_variant 6/7
TGFB2NR_138149.2 linkuse as main transcriptn.2293C>T non_coding_transcript_exon_variant 7/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TGFB2ENST00000366930.9 linkuse as main transcriptc.958C>T p.Arg320Cys missense_variant 6/71 NM_003238.6 ENSP00000355897.4 P61812-1
TGFB2ENST00000366929.4 linkuse as main transcriptc.1042C>T p.Arg348Cys missense_variant 7/81 ENSP00000355896.4 P61812-2
TGFB2ENST00000479322.1 linkuse as main transcriptn.442C>T non_coding_transcript_exon_variant 4/53

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
show subpopulations
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:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Loeys-Dietz syndrome 4 Pathogenic:5
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 06, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMay 28, 2019The 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. -
Likely pathogenic, criteria provided, single submitterclinical testing3billion-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. -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterOct 29, 2024Criteria applied: PS4_MOD,PM2_SUP,PM5_SUP,PP3,PP4 -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 03, 2023This 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. -
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 25, 2024The p.R320C variant (also known as c.958C>T), located in coding exon 6 of the TGFB2 gene, results from a C to T substitution at nucleotide position 958. The arginine at codon 320 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant (also referred to as NM_001135599.2:c.1042C>T, p.R348C) was reported in unrelated individuals with thoracic aortic aneurysm and dissection with and without mild systemic connective tissue disease features, and segregated with disease in families (Gago-Díaz M et al. Clin. Chim. Acta, 2014 Nov;437:88-92; Al Maskari R et al. Eur. J. Hum. Genet., 2016 01;25:157-160). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
TGFB2-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 18, 2024The TGFB2 c.958C>T variant is predicted to result in the amino acid substitution p.Arg320Cys. This variant was reported in two unrelated individuals with aortic aneurysms and dissections, which are characteristic features of Loeys-Dietz syndrome, type 4 (reported as c.1042C>T, p.Arg348Cys in Gago-Díaz et al. 2014. PubMed ID: 25046559; Al Maskari et al. 2016. PubMed ID: 27782106). This variant is found in a highly conserved region of the TGFB2 protein, and was shown to segregate with disease in both families. Immunofluorescence experiments noted increased TGFB2 and TGFB1 protein levels compared to controls in the aorta of an affected individual (Al Maskari et al. 2016. PubMed ID: 27782106). Enhanced TGFB signaling is believed to play a role in aortic dilation and aneurysms. An alternate amino acid change at this same position (p.Arg348His in NM_001135599.3) was found in another individual with Loeys-Dietz syndrome (Table 2, Haug et al. 2021. PubMed ID: 33418956). This variant has not been reported in a large population database, indicating this variant is rare. This variant has interpretations of likely pathogenic (3) and pathogenic (2) in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/495213/). We interpret this variant as likely pathogenic. -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxDec 23, 2022Reported 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;.
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553303352; hg19: chr1-218610710; API