Submissions for variant NM_004612.4(TGFBR1):c.343+3A>G

gnomAD frequency: 0.00002  dbSNP: rs374717754

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002222332	SCV000250853	uncertain significance	not provided	2022-04-13	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing
Invitae	RCV000530331	SCV000658849	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the TGFBR1 gene. It does not directly change the encoded amino acid sequence of the TGFBR1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374717754, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 213854). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000530331	SCV000739744	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-03-29	criteria provided, single submitter	clinical testing	The c.343+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 2 in the TGFBR1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000530331	SCV001347625	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-01-29	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000196672	SCV000280491	uncertain significance	not specified	2013-03-13	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. IVS2+3 A>G (c.343+3 A>G) in TGFBR1 Based on the data reviewed below we consider this variant to be a variant of uncertain significance, The variant appears to be novel. The variant changes the A at the +3 position of the splice junction to a G. While this position in the splice junction is most frequently an A it is also often a G. In TGFBR1 specificaly the A at c.343+3 is conserved across species. The testing lab reports that multiple in silico splice algorithms predict that this variant does not affect splicing. There are two splice variants listed in the professional version of HGMD. We have access to one in the public version and this appears to be reported as associated with cancer risk. Per a "clinical utility gene card" in the European Journal of Human Genetics by Dr. Loeys' group, splicing variants have been reported in association with disease (Arslan-Kirchner et al 2011). In total the variant has not been seen in ~6500 individuals from publicly available population datasets. In addition, splicing variants as a class appear to be rare in this gene. This variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of March 11th, 2013). Only one splicing variant is listed in this database: c.341+1 G>A (rs144775920). That variant was seen in 1 out of ~6500 individuals. No nonsense or frameshift variants are listed in NHLBI ESP. IVS2+3 A>G is also not listed in dbSNP or 1000 genomes (as of March 11th, 2013).