ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.184C>T (p.Arg62Cys) (rs25403)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035129 SCV000058769 pathogenic Marfan syndrome 2006-10-28 criteria provided, single submitter clinical testing
GeneDx RCV000493952 SCV000582883 likely pathogenic not provided 2016-01-14 criteria provided, single submitter clinical testing This variant has been published in association with isolated ectopia lentis (EL) and Marfan syndrome (Korkko et al., 2002; Katzke et al., 2002; Yu et al., 2006; Zhao et al., 2013). Katzke et al. (2002) identified R62C in 3 unrelated individuals: one individual with b/l EL and who also had aortic dilation and arachnodactly; second individual with b/l EL, and no cardiac or skeletal involvement; and third individual was being evaluated for suspected MFS. Yu et al.(2006) reported this variant in a four generation family of Chinese ancestry (Zhejiang Province) with isolated b/l EL with no cardiac involvement; R62C was identified in all affected individuals (n=6) and was absent from unaffected family members (n=14) and 100 unrelated normal controls. Zhao et al. (2013) also described this variant in a five generation family of Chinese ancestry (Shaanxi Province) with a diagnosis of isolated EL and R62C was found to segregate in five affected living family members and did not segregate with two of the living unaffected members tested. Korkko et al. (2002) reported this variant (as R114C, due to alternate nomenclaure) in one individual with Marfan syndrome. Also, this variant has also been reported as pathogenic in one individual referred for genetic testing at an external laboratory (Landrum et al., 2014).The R62C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R62C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Lastly, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is likely pathogenic
Ambry Genetics RCV000617246 SCV000738849 pathogenic Cardiovascular phenotype 2018-02-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses)
Center for Human Genetics, Inc RCV000035129 SCV000781317 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000697256 SCV000825856 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 62 of the FBN1 protein (p.Arg62Cys). The arginine residue is moderately 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 be de novo in an individual affected with ectopia lentis (PMID: 12203992) and has been described to segregate with the disease in two families (PMID: 16765689, 22950452). This variant has also been found in several individuals with FBN1-related disease (PMID: 11826022, 12203992, 25053872, 25944730, 27611364). This variant is also known as R114C in the literature. ClinVar contains an entry for this variant (Variation ID: 42295). 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"). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000035129 SCV000786806 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.