ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.343+3A>G (rs374717754)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196672 SCV000250853 likely benign not specified 2013-02-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000530331 SCV000658849 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-11-27 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs374717754, ExAC 0.002%). This variant has not been reported in the literature in individuals with TGFBR1-related disease. ClinVar contains an entry for this variant (Variation ID: 213854). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000618795 SCV000739744 uncertain significance Cardiovascular phenotype 2018-09-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color 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).

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