ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2489G>C (p.Cys830Ser) (rs397515774)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035144 SCV000058785 likely pathogenic Marfan syndrome 2012-12-21 criteria provided, single submitter clinical testing The c.2489G>C (p.Cys830Ser) has not been previously identified by our laboratory , but has been reported in the Korean Mutation Database (mutation ID KM0000769) in a patient with Marfan syndrome. In addition, the same amino acid change (p.Cy s830Ser) caused by a different DNA change (c.2488T>A) has been identified in one patient with clinical features of Marfan syndrome that met Ghent criteria (Sthe neur 2009). The variant identified in this individual has not been identified in large and broad populations by the NHLBI Exome Sequencing Project (http://evs.g Computational analyses (biochemical amino acid properties , conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Cys830Ser varia nt may impact the normal function of the protein, though this information is not predictive enough to conclusively determine pathogenicity. In addition, this va riant affects a cysteine residue; cysteine substitutions are a common finding in individuals with Marfan syndrome (Schrijver 1999). In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance.
Invitae RCV000697797 SCV000826428 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 830 of the FBN1 protein (p.Cys830Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 42310). A different variant (c.2488T>A) giving rise to the same protein effect observed here (p.Cys830Ser) has been reported to be de novo in an individual with Marfan syndrome (PMID: 19293843), indicating that this residue may be critical for protein function. This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 10486319, 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Cys830Tyr) has been reported in an individual with Marfan syndrome (PMID: 16476890). For these reasons, this variant has been classified as Pathogenic.

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