ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2581C>T (p.Arg861Ter) (rs140583)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254863 SCV000322260 pathogenic not provided 2016-07-26 criteria provided, single submitter clinical testing The R861X variant in the FBN1 gene has been reported many times in individuals partially or completely fulfilling Ghent criteria for Marfan syndrome (Liu et al., 1997; Arbustini et al., 2005; Comeglio et al., 2007; Chung et al., 2009; Magyar et al., 2009; Stheneur et al., 2009; Lebreiro et al., 2011). R861X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the FBN1 gene have been reported in HGMD in association with Marfan syndrome (Stenson et al., 2014). Furthermore, the R861X pathogenic 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, R861X in the FBN1 gene is interpreted as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507994 SCV000603640 pathogenic not specified 2016-10-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590228 SCV000695488 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.2581C>T (p.Arg861X) variant results in a premature termination codon, predicted to cause a truncated or absent FBN1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 121196 control chromosomes (ExAC). Multiple publications cite the variant in affected individuals, along with multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000620881 SCV000738785 pathogenic Cardiovascular phenotype 2018-10-29 criteria provided, single submitter clinical testing The p.R861* pathogenic mutation (also known as c.2581C>T), located in coding exon 21 of the FBN1 gene, results from a C to T substitution at nucleotide position 2581. This changes the amino acid from an arginine to a stop codon within coding exon 21. This alteration has been reported in multiple individuals with Marfan syndrome (MFS) or MFS-related phenotypes (Liu WO et al. Genet Test. 1997-1998;1(4):237-42; Schrijver I et al. Am J Hum Genet. 2002;71(2):223-37; Arbustini E et al. Hum Mutat. 2005;26(5):494; Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8; Katzke S et al. Hum Mutat 2002; 20(3):197-208; Magyar I et al. Hum Mutat. 2009;30(9):1355-64; Guo J et al. Sci Rep. 2015;5:13115). One study of patient-derived induced pluripotent stem cells exhibiting this mutation reported impact to microfibril formation, osteogenesis, contractility, and calcium influx, with rescue of some defects in mutation-corrected cells (Park JW et al. Int J Biol Sci. 2017;13(5):588-603). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000767971 SCV000898698 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 2018-08-10 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon 22 p.Arg861* (c.2581C>T): This variant has been reported in the literature in several individuals with features or a clinical diagnosis of Marfan syndrome, including at least 1 individual as de novo (Katzke 2002 PMID:12203992, Schrijver 2002 PMID:12068374, Arbustini 2005 PMID:16222657, Comeglio 2007 PMID:17657824, Chung 2009 PMID:19533785, Magyar 2009 PMID:19618372, Stheneur 2009 PMID:19293843, Guo 2015 PMID:26272055). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:265401). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Dietz 2017 PMID: 20301510). In summary, this variant is classified as pathogenic.
Invitae RCV000810561 SCV000950774 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-05-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg861*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo an individual affected with Marfan syndrome (PMID: 19293843) and has been observed in several individuals with Marfan syndrome, clinical features consistent with Marfan syndrome, or thoracic aortic aneurysm and dissection (PMID: 10464652, 26272055, 2005308, 16222657, 17657824). ClinVar contains an entry for this variant (Variation ID: 265401). Experimental studies have shown that this nonsense change causes compromised osteogenesis, reduced contraction, and altered calcium signaling in cells (PMID: 28539832). Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). For these reasons, this variant has been classified as Pathogenic.
Department of Vascular Biology,Beijing Anzhen Hospital RCV001374789 SCV001439554 likely pathogenic Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000614836 SCV000731243 pathogenic Familial thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
Center for Medical Genetics Ghent,University of Ghent RCV000663557 SCV000786868 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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