ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.8226+1G>A (rs398122833)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000631959 SCV000753062 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-09-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 65 of the FBN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individuals affected with Marfan syndrome and lipodystrophy (PMID: 24613577). ClinVar contains an entry for this variant (Variation ID: 225629). A different variant affecting this nucleotide (c.8226+1G>T) has been determined to be pathogenic (PMID: 21594993). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Experimental studies have shown that this intronic change causes the skipping of exon 65 during mRNA splicing (PMID: 24613577). This variant does not result in nonsense mediated decay, but creates a truncated protein that lacks the Furin site. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000210934 SCV000267618 pathogenic Marfan lipodystrophy syndrome 2016-04-28 no assertion criteria provided literature only
Center for Medical Genetics Ghent,University of Ghent RCV000664017 SCV000787405 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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