ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.8038C>T (p.Arg2680Cys) (rs794728283)

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
GeneDx RCV000181625 SCV000233928 likely pathogenic not provided 2016-12-21 criteria provided, single submitter clinical testing The R2680C likely pathogenic variant in the FBN1 gene has been previously reported in association with Marfan syndrome (Grossfield et al., 1993; Palz et al., 2000; Comeglio et al., 2007). This variant occurred de novo in a 24 year old whose features included tall stature, scoliosis, pectus excavatum, ectopia lentis, hypermobility and mitral valve prolaspe, but no cardiovascular involvement (Palz et al., 2000). Comeglio et al. (2007) reported this variant in a 7 year old with incomplete Marfan syndrome", because the Ghent criteria were not completely fulfilled. Moreover, this variant was absent from 160 ethnically-matched chromosomes from unrelated individuals (Comeglio et al., 2007), and R2680C 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. R2680C results in a non-conservative amino acid substitution of positively charged Arginine to a neutral, polar Cysteine at a position that is conserved across species. This substitution involves a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and alter the structure and function of the protein. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Pathogenic variants in nearby residues (C2686R, C2686F) have been reported in HGMD in association with Marfan syndrome (Stenson et al., 2014), further supporting the functional importance of cysteine residues in this particular region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded"
Ambry Genetics RCV000241917 SCV000318734 likely pathogenic Cardiovascular phenotype 2013-06-12 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,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other data supporting pathogenic classification
Invitae RCV000476927 SCV000544872 likely pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-03-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2680 of the FBN1 protein (p.Arg2680Cys). 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 sequence change was reported in individuals affected with FBN1-related conditions (PMID: 17657824, 17679947), and was reported to occur de-novo in an individual affected with Marfan's, but without cardiovascular involvement (PMID: 10756346), This variant has also been reported in individuals in the FBN1- Universal Mutation Database (PMID: 12938084). ClinVar contains an entry for this variant (Variation ID: 200127). 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). In summary, this variant is a rare missense change that potentially affects protein structure and stability and has been reported in individuals affected with a range of FBN1-associated conditions. However, in the absence of functional or segregation data, it has been classified as Likely Pathogenic
Center for Human Genetics, Inc RCV000659584 SCV000781422 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770651 SCV000902109 likely pathogenic Thoracic aortic aneurysm and aortic dissection 2016-12-07 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000659584 SCV000787392 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.