Submissions for variant NM_003238.6(TGFB2):c.904C>T (p.Arg302Cys)

dbSNP: rs869312903

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000210476	SCV000266538	pathogenic	Loeys-Dietz syndrome 4		criteria provided, single submitter	research
GeneDx	RCV000255040	SCV000321960	pathogenic	not provided	2022-05-31	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000210476	SCV000816450	pathogenic	Loeys-Dietz syndrome 4	2023-10-04	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000210476	SCV001160164	likely pathogenic	Loeys-Dietz syndrome 4	2018-12-28	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002372209	SCV002687672	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-04-29	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017492	SCV004848465	likely pathogenic	Loeys-Dietz syndrome	2020-08-24	criteria provided, single submitter	clinical testing	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.
GenomeConnect, ClinGen	RCV001824688	SCV002075071	not provided	Aortic aneurysm, familial thoracic, TGFB2 related		no assertion provided	phenotyping only	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.