ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1633C>T (p.Arg545Cys) (rs730880099)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157225 SCV000206949 pathogenic Marfan syndrome 2015-11-06 criteria provided, single submitter clinical testing
GeneDx RCV000256026 SCV000321630 pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing The R545C pathogenic variant in the FBN1 gene has been reported in multiple individuals with Marfan syndrome (Hayward et al., 1997; Comeglio et al., 2002; Jin et al., 2007; Aragon-Martin et al., 2010). Hayward et al. (1997) describes a large 4 generation family in which R545C segregates with Marfan syndrome in more than 10 individuals who are described as having ocular, skeletal and cardiovascular involvement. R545C results in a non-conservative amino acid substitution of Cysteine at a position that is conserved across species. Moreover, the R545C variant introduces a Cysteine residue in the calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in the calcium-binding EGF-like domain represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Finally, the R545C variant was not observed 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. In summary, R545C in the FBN1 gene is interpreted as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507510 SCV000603631 pathogenic not specified 2017-03-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589881 SCV000695462 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2016-10-10 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.1633C>T (p.Arg545Cys) variant involves the alteration of a highly conserved nucleotide and is located in the Ca2+-binding EGF-like #4 domain with 5/5 in silico tools predicting a deleterious outcome. This change disrupts disulfide bonds 541-555 (C4) which affects the secondary or tertiary structure and possibly impairing fibrillin interactions. The variant is absent from control dataset of ExAC and but has been reported in numerous affected individuals predominantly with isolated EL via published reports, although several pts with classical MFS have also been reported, including within families presenting with EL. Two published reports clearly indicate segregation of the variant with the disease (Hayward, 1997 and Li, 2016). The variant has been cited by several reputable databases/clinical laboratories as Pathogenic. Taking together, the variant was classified as Pathogenic.
Ambry Genetics RCV000621314 SCV000738771 pathogenic Cardiovascular phenotype 2017-11-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Strong segregation with disease (lod >3 = >10 meioses),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000631935 SCV000753038 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 545 of the FBN1 protein (p.Arg545Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Marfan syndrome in a several families and has been found in several individuals affected with Marfan syndrome and ectopia lentis (PMID: 9338581, 27353645, 12446365, 15241795, 19159394, 17679947, 20564469, 27611364). ClinVar contains an entry for this variant (Variation ID: 180352). This variant generates a cysteine residue in 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: 4750422, 16677079). Cysteine creating variants in these domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763358 SCV000894048 pathogenic Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2018-10-31 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000157225 SCV000786772 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.