ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.1462T>C (p.Cys488Arg)

dbSNP: rs1555400373
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547735 SCV000627839 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2022-07-12 criteria provided, single submitter clinical testing This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 18435798; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 488 of the FBN1 protein (p.Cys488Arg). ClinVar contains an entry for this variant (Variation ID: 457162). For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function.
Fulgent Genetics, Fulgent Genetics RCV000763359 SCV000894049 likely pathogenic Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798874 SCV002041951 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-09-19 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent, University of Ghent RCV000663458 SCV000786751 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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