ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.3838+2T>C

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002364044 SCV002626014 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2015-12-24 criteria provided, single submitter clinical testing The c.3838+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 30 in the FBN1 gene. This alteration was reported in one family with Marfan syndrome in our laboratory. Since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
All of Us Research Program, National Institutes of Health RCV004005642 SCV004822542 likely pathogenic Marfan syndrome 2023-04-28 criteria provided, single submitter clinical testing This variant causes a T to C nucleotide substitution at the +2 position of intron 31 of the FBN1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to impair the function of FBN1 protein by disrupting the normal expression of exon 31. Multiple pathogenic missense variants have been reported in this exon (ClinVar), indicating the functional and clinical importance of the region that may be affected by this variant. This variant has been reported in an individual affected with thoracic aortic aneurysm and aortic dissection (PMID: 34498425). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant (c.3838+1G>A) that affects the same exon 31 splice donor site has been reported in two individuals affected with neonatal Marfan syndrome (PMID: 20803651, 26796135). Loss of FBN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

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