ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2293G>A (p.Asp765Asn)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284984 SCV001471086 likely pathogenic none provided 2020-01-06 criteria provided, single submitter clinical testing The FBN1 c.2293G>A; p.Asp765Asn variant is reported in the literature in at least one individual affected with Marfan syndrome (Robinson 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The nucleotide at position 2293 is highly conserved, and is the last nucleotide in exon 18. Computational analyses (Alamut v.2.11) predict that this variant may impact splicing by disrupting the canonical splice donor site of intron 18, which is likely to negatively impact gene function. Indeed, RNA analyses from a patient sample show altered splicing at a cryptic site that results in a deletion of 4 nucleotides, so this variant is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be likely pathogenic. References: Robinson DO et al. Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities. Clin Genet. 2012 Sep;82(3):223-31.

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