Submissions for variant NM_003238.6(TGFB2):c.958C>T (p.Arg320Cys)

dbSNP: rs1553303352

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000585795	SCV001160578	likely pathogenic	Loeys-Dietz syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing	The 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000585795	SCV001420990	pathogenic	Loeys-Dietz syndrome 4	2023-03-03	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 495213). 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. This variant is not present in population databases (gnomAD no frequency). This 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).
GeneDx	RCV002225683	SCV002504220	likely pathogenic	not provided	2022-12-23	criteria provided, single submitter	clinical testing	Reported 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)
3billion, Medical Genetics	RCV000585795	SCV004013720	likely pathogenic	Loeys-Dietz syndrome 4		criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV004678752	SCV005170142	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-04-25	criteria provided, single submitter	clinical testing	The 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000585795	SCV005397100	likely pathogenic	Loeys-Dietz syndrome 4	2024-10-29	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM2_SUP,PM5_SUP,PP3,PP4
OMIM	RCV000585795	SCV000693725	pathogenic	Loeys-Dietz syndrome 4	2018-03-06	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004730985	SCV005335546	likely pathogenic	TGFB2-related disorder	2024-04-18	no assertion criteria provided	clinical testing	The 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.