ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7339G>A (p.Glu2447Lys) (rs137854464)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000417099 SCV000494654 pathogenic Marfan syndrome 2015-11-04 criteria provided, single submitter clinical testing Patient with suspicion of Marfan syndrome. The identification of a missense pathogenic mutation in the FBN1 gene confirms the diagonstic of Marfan syndrome
GeneDx RCV000422790 SCV000518161 likely pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing The E2447K likely pathogenic variant in the FBN1 gene has been reported previously in association with ectopia lentis and Marfan syndrome (Kainulainen et al., 1994; Lonnqvist et al., 1994; Comeglio et al., 2007; Aragon-Martin et al., 2010; Franken et al., 2016). The E2447K variant (also reported as E1549K due to alternate nomenclatures) has been described in a four generation British family in which three living family members had diagnoses of ectopia lentis with some skeletal and ocular involvement but no cardiovascular findings, therefore not meeting Ghent criteria for Marfan syndrome (Kainulainen et al., 1994; Lonnqvist et al., 1994). The variant was found to segregate in both family members with ectopia lentis and family members without ectopia lentis but with skeletal findings, and was absent from clinically unaffected relatives (Kainulainen et al., 1994; Lonnqvist et al., 1994). This variant has also been observed in three individuals meeting Ghent criteria for Marfan syndrome and was absent in 160 published control individuals (Comeglio et al., 2007; Franken et al., 2016); however segregation data was not available for these individuals. The E2447K variant was not observed in the Exome Aggregation Consortium or in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E2447K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs within a calcium-binding EGF-like domain at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the E2447K variant does not affect a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003).Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required. Clinical correlation with this test result is recommended.
Invitae RCV000695313 SCV000823803 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-05-10 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2447 of the FBN1 protein (p.Glu2447Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with ectopia lentis in an affected family (PMID: 8188302, 8136837) and has been reported in several individuals affected with ectopia lentis or Marfan syndrome (PMID: 20564469, 11826022, 17657824, 26787436). This variant is also known as Glu1549Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 16437). In an experimental study this variant was shown to affect fibrillin catabolism (PMID: 10229672). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000017899 SCV000038178 pathogenic Ectopia lentis, isolated, autosomal dominant 2007-09-01 no assertion criteria provided literature only

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