ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.1850G>A (p.Cys617Tyr)

dbSNP: rs1555399836
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen RCV000663505 SCV004123033 pathogenic Marfan syndrome 2023-11-16 reviewed by expert panel curation NM_00138 c.1850G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 617 (p.Cys617Tyr). This variant was found in a proband with ectopia lentis, thoracic aortic aneurysm and dissection, and skeletal features (PP4; Bichat internal data). It has also been reported in the literature in two probands, one meeting revised Ghent criteria for Marfan syndrome and one with EL and a systemic score of 7 (PS4_moderate; PMIDs: 27906200, 33483584). This variant was found to be de novo with confirmation of maternity and paternity in an individual with Marfan syndrome, without specific phenotypic features available (PS2_supporting; deCODE genetics internal data, ClinVar Variation ID: 495563). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium binding EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Several other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys617Arg, p.Cys617Gly, p.Cys617Ser). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_moderate, PM2_supporting, PS2_supporting, PP2, PP3, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587166 SCV000695469 uncertain significance not provided 2016-03-15 criteria provided, single submitter clinical testing
Invitae RCV001070382 SCV001235608 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2021-09-02 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent, University of Ghent RCV000663505 SCV000786807 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
deCODE genetics, Amgen RCV000663505 SCV003915952 pathogenic Marfan syndrome 2023-04-10 no assertion criteria provided case-control The p.(Cys617Tyr) variant occurred de novo in an individual diagnosed with Marfan syndrome, maternity and paternity confirmed. Applied ACMG criteria: PS2, PM2, PP2, PP4, PP5_strong

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