ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6163+2dup (rs794728315)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181670 SCV000233973 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2014-07-18 criteria provided, single submitter clinical testing c.6163+2dupT: IVS50+2_50+3insT in intron 50 of the FBN1 gene (NM_000138.4)Although the c.6163+2_6163+3insT c.6163+2dupT mutation has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, in silico splice prediction algorithms predict that this mutation destroys the canonical splice donor site in intron 50, causing abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the FBN1 gene have been reported in association with Marfan syndrome. In summary, c.6163+2dupT in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590701 SCV000695577 uncertain significance not provided 2017-08-04 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.6163+2dupT variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant of interest has not been found in a large, broad control population, ExAC in 121310 control chromosomes. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Considering the in-silico predictions and the potential of this variant to destroy the canonical splice donor site in intron 50, thus affecting gene splicing, this variant is classified as possibly pathogenic, until more functional and clinical studies become available.
Color Health, Inc RCV000181670 SCV001348904 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-07-27 criteria provided, single submitter clinical testing
Invitae RCV001239673 SCV001412564 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-06-28 criteria provided, single submitter clinical testing This sequence change falls in intron 50 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 200167). 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 may disrupt the consensus splice site, 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.