ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4460-8G>A (rs193922204)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507229 SCV000603671 likely pathogenic not specified 2017-04-03 criteria provided, single submitter clinical testing
Blueprint Genetics, RCV000029737 SCV000263915 pathogenic Marfan syndrome 2015-11-13 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768217 SCV000898693 likely 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 2018-03-15 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon 37 c.4460-8G>A: This variant has been reported in the literature in at least 3 individuals with features or a clinical suspicion of Marfan syndrome, segregating with disease in 2 affected family members (Loeys 2001 PMID:11700157, Pepe 2007 PMID:18087243, Stheneur 2009 PMID:19293843). This variant is present in 1/33572 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs193922204). This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:36075). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Additional studies suggest that this variant may activate a cryptic acceptor site and impact the protein (Loeys 2001 PMID:11700157, Pepe 2007 PMID:18087243). However, further studies are needed to understand its impact. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000029737 SCV000787066 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000429823 SCV000515903 likely pathogenic not provided 2019-01-11 criteria provided, single submitter clinical testing A likely pathogenic variant has been identified in the FBN1 gene. The c.4460-8 G>A variant has been reported in association with classic Marfan syndrome (Loeys et al., 2001; Stheneur et al., 2009). It has also been reported in three affected individuals of one family with ectopia lentis and systemic features of Marfan syndrome but without aortopathy (Pepe et al., 2007). In addition, the c.4460-8 G>A variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). This single nucleotide substitution occurs upstream of the natural splice acceptor site in intron 36 and creates a new cryptic splice acceptor site. Two publications independently reported that cDNA sequence analysis demonstrated the result of this variant to be in-frame insertion of 6 nucleotides into the coding sequence (c.4459_4460insTTTTAG) (Loeys et al., 2001; Pepe et al., 2007). Other in-frame insertions and other splice site variants in the FBN1 gene have been reported in HGMD in association with FBN1-related disorders (Stenson et al., 2014).
Integrated Genetics/Laboratory Corporation of America RCV000029737 SCV000052390 likely pathogenic Marfan syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV000524498 SCV000544952 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-10-17 criteria provided, single submitter clinical testing This sequence change falls in intron 36 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Marfan syndrome (PMID: 11700157, 19293843, Invitae). This variant is also known as IVS35-8G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 36075). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this intronic variant is absent from the population, has been observed in several affected individuals, and it is predicted to affect mRNA splicing. For these reasons, this variant has been classified as Pathogenic.

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