ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4460A>C (p.Asp1487Ala)

dbSNP: rs1555397216
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre of Medical Genetics, University of Antwerp RCV000663730 SCV002025319 likely pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PS6, PP4
GeneDx RCV003228975 SCV003925989 uncertain significance not provided 2022-11-21 criteria provided, single submitter clinical testing Reported in a patient with Marfan syndrome in published literature (Baetens et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20591885, 21542060)
Labcorp Genetics (formerly Invitae), Labcorp RCV003767933 SCV004570882 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2022-11-10 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1487 of the FBN1 protein (p.Asp1487Ala). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 21542060; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp148 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30838813; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 549234).
Center for Medical Genetics Ghent, University of Ghent RCV000663730 SCV000787067 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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