Submissions for variant NM_003242.6(TGFBR2):c.95-2A>G

gnomAD frequency: 0.00001  dbSNP: rs779131465

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001183529	SCV001349286	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-16	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 1 of the TGFBR2 gene. A functional RNA study has shown that this variant activates a cryptic splice acceptor 18 nucleotides downstream of the native intron 1 splice acceptor site, leading to an in-frame deletion of codon 32-37 in the extracellular domain (PMID: 15731757). Protein functional studies have not been reported for this variant, however, a study in primary dermal fibroblasts from a carrier individual reported a normal rate and level of phosphorylation of the downstream target Smad2, an essential mediator of TGF-beta signaling (PMID: 15731757). This variant has been reported in individuals affected with Loeys-Dietz syndrome (PMID: 15731757), thoracic aortic aneurysm and dissection (PMID: 31915033), epilepsy (PMID: 33391346) and adolescent idiopathic scoliosis (PMID: 34958866). This variant has also been reported in a few individuals affected with conditions that are not known to be associated with TGFBR2 (PMID: 35727495). This variant has been identified in 3/282182 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000013338	SCV001434902	likely pathogenic	Loeys-Dietz syndrome 2	2018-10-12	criteria provided, single submitter	clinical testing	This c.170-2A>G variant in the TGFBR2 gene is predicted to disrupt a canonical splice donor site and thus alter the wild type mRNA splicing. This variant has been reported in one child affected with Loeys-Dietz Syndrome (PMID 15731757). This variant is extremely rare in general population.Therefore, this c.170-2A>G variant in the TGFBR2 gene is classified as likely pathogenic.
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374778	SCV001439495	likely pathogenic	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001183529	SCV003265410	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-11-10	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs779131465, gnomAD 0.02%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 2 (PMID: 15731757). ClinVar contains an entry for this variant (Variation ID: 12513). Disruption of this splice site has been observed in individual(s) with aortic dissection and/or Loeys-Dietz syndrome (PMID: 15731757, 33083483, 33824467). In at least one individual the variant was observed to be de novo. This sequence change affects an acceptor splice site in intron 1 of the TGFBR2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 6 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
CeGaT Center for Human Genetics Tuebingen	RCV003221782	SCV003916415	likely pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	TGFBR2: PVS1:Strong, PM6, PS4:Moderate, PM2:Supporting
OMIM	RCV000013338	SCV000033585	pathogenic	Loeys-Dietz syndrome 2	2005-03-01	no assertion criteria provided	literature only