ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5372G>A (p.Cys1791Tyr) (rs886038848)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000253774 SCV000318525 likely pathogenic Cardiovascular phenotype 2017-06-07 criteria provided, single submitter clinical testing The p.C1791Y variant (also known as c.5372G>A), located in coding exon 43 of the FBN1 gene, results from a G to A substitution at nucleotide position 5372. The cysteine at codon 1791 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #25 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This variant was described in an 38-year-old individual with classic Marfan syndrome (MFS) (Loeys B et al. Arch. Intern. Med. 2001;161(20):2447-54). It was also reported in a study that screened samples with known FBN1 genotypes (Mátyás G et al. Hum. Mutat. 2002;19(4):443-56). Two other alterations in the same codon (p.C1791F and p.C1791R) have been associated with MFS (Howarth R et al. Genet. Test. 2007;11(2):146-52; Rommel K et al. Hum. Mutat. 2005;26(6):529-39). Furthermore, internal structural analysis indicates that this alteration disrupts a disulfide bond and is structurally destabilizing (Lee SS et al. Structure. 2004;12(4):717-29). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781361 SCV000919338 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2018-12-17 criteria provided, single submitter clinical testing Variant summary: FBN1 c.5372G>A (p.Cys1791Tyr) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246008 control chromosomes. c.5372G>A has been reported in the literature in individuals affected with Marfan Syndrome. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000663780 SCV000787131 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.