Submissions for variant NM_000138.5(FBN1):c.2581C>T (p.Arg861Ter)

dbSNP: rs140583

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254863	SCV000322260	pathogenic	not provided	2021-01-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies using induced pluripotent stem cells demonstrated that this variant decreases FBN1 protein expression, impairs osteogenesis, reduces contractility and alters calcium signaling in derivative mesenchymal stem cells and/or vascular smooth muscle cells (Park et al., 2017); Reported in ClinVar as pathogenic (ClinVar Variant ID# 265401; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 26272055, 29357934, 29543232, 10464652, 12203992, 12068374, 19293843, 22005308, 19618372, 19533785, 16222657, 17657824, 28539832)
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	RCV000614836	SCV000738785	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	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 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-11-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810561	SCV000950774	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-26	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This premature translational stop signal has been observed in individual(s) with Marfan syndrome, clinical features consistent with Marfan syndrome, or thoracic aortic aneurysm and dissection and Marfan syndrome (PMID: 2005308, 10464652, 16222657, 17657824, 19293843, 26272055). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265401). 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 of Medical Genetics, University of Antwerp	RCV000663557	SCV002025540	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS1, PP4
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