ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1468+5G>A (rs397515757)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617138 SCV000318198 pathogenic Cardiovascular phenotype 2016-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Blueprint Genetics RCV000035117 SCV000206958 pathogenic Marfan syndrome 2014-05-16 no assertion criteria provided clinical testing
Blueprint Genetics RCV000181432 SCV000927425 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000251716 SCV000901057 pathogenic Thoracic aortic aneurysm and aortic dissection 2017-04-11 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000035117 SCV000781331 likely pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000035117 SCV000786754 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000251716 SCV000731214 likely pathogenic Thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000035117 SCV000863468 pathogenic Marfan syndrome 2018-12-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515263 SCV000611190 pathogenic Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000181432 SCV000233734 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing The c.1468+5 G>A pathogenic variant in the FBN1 gene has previously been reported multiple timesin association with Marfan syndrome or a Marfan-like phenotype (Liu et al., 1997-1998; Comeglio etal., 2007; Vis et al., 2009; Baetens et al., 2011; Aalberts et al., 2014; Baudhuin et al., 2015; Proost etal., 2015; Latasiewicz et al., 2016). Vis et al. (2009) reported c.1468+5 G>A in a patient withTrisomy 21 and suspected Marfan syndrome, as well as in her affected father. In addition, this variantoccurred apparently de novo in a 22 year-old female with an abdominal aortic dissection and epidermaland skeletal features of Marfan syndrome (Baudhuin et al., 2015). Using complementary DNA fromsurgical specimens, Ogawa et al. (2011) demonstrated that c.1468+5 G>A destroys the natural splicedonor site and activates a latent splice donor site within the preceding exon, resulting in a new splicedonor site and premature truncation. Other downstream splice site variants in the FBN1 gene havebeen reported in HGMD in association with Marfan syndrome (Stenson et al., 2014). Furthermore, thec.1468+5 G>A variant was not observed in large population cohorts (Lek et al., 2016; Exome VariantServer).
Invitae RCV000631905 SCV000753008 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-11-22 criteria provided, single submitter clinical testing This sequence change falls in intron 12 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 several individuals affected with FBN1-related disease, and has been found to be de novo in an individual with aortic dilatation and skeletal features (PMID: 10464652, 17627385, 17657824, 25101912, 25907466). This variant is also knows=n as c.IVS11+5G >A in the literature. ClinVar contains an entry for this variant (Variation ID: 42284). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change leads to the inactivation of the natural donor splice site and the usage of an out-of-frame cryptic splice site (PMID: 21907952). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035117 SCV000058757 pathogenic Marfan syndrome 2017-02-23 criteria provided, single submitter clinical testing The c.1468+5G>A variant in FBN1 has been reported in 9 individuals with clinical features of Marfan syndrome (Aalberts 2014, Baetens 2011, Comeglio 2007, Liu 19 97-1998, LMM data). It has not been identified in large population studies. In a ddition, this variant has segregated with disease in 5 affected individuals from one family tested by our laboratory. The c.1468+5G>A variant is located in the 5' splice region and RNA studies have revealed this splice site variant leads to abnormal splicing and exon skipping in FBN1 (Aalberts 2014, Ogawa 2011, Liu 199 7-1998), resulting in an abnormal or absent protein. Heterozygous loss of functi on of the FBN1 gene is an established disease mechanism in Marfan syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosoma l dominant Marfan syndrome based on its recurrence in multiple affected individu als, segregation in families, extremely low allele frequency in the general popu lation, and functional impact on splicing.

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