ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618795 SCV000739744 uncertain significance Cardiovascular phenotype 2016-05-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
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 Thoracic aortic aneurysm and aortic dissection 2017-05-10 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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