ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.8226+5G>A (rs193922243)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000631943 SCV000753046 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2017-10-06 criteria provided, single submitter clinical testing This sequence change falls in intron 65 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 been reported in individuals affected with Marfan syndrome or aortic dilatation, being described as de novo in two of them (PMID: 27884935, Invitae). 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. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284854 SCV001470947 likely pathogenic none provided 2019-11-11 criteria provided, single submitter clinical testing The FBN1 c.8226+5G>A variant (rs193922243) is reported in the literature in an individual affected with Marfan syndrome (Miller 2017). Familial testing of the affected individual did not find the variant in either parent, suggesting a de novo origin in this individual (Miller 2017). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Based on available information, this variant is considered to be likely pathogenic. References: Miller KA et al. Diagnostic value of exome and whole genome sequencing in craniosynostosis. J Med Genet. 2017 Apr;54(4):260-268.

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