ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6658C>T (p.Arg2220Ter) (rs113001196)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000181574 SCV000885419 pathogenic not provided 2018-06-11 criteria provided, single submitter clinical testing The FBN1 c.6658C>T; p.Arg2220Ter variant (rs113001196) has been described in several individuals affected with Marfan syndrome (Attanasio 2013, Collod-Beroud 2003, Comeglio 2007, Matsukawa 2001, Ogawa 2011, Wang 2013). It is reported as pathogenic in ClinVar (Variation ID: 42407), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. Pathogenic FBN1 variants are most commonly causative for Marfan syndrome (MFS); clinical manifestations are variable. Additionally, other phenotypes including neonatal Marfan syndrome, mitral valve prolapse syndrome, MASS syndrome, thoracic aortic aneurysms and aortic dissections (TAAD), Shprintzen-Goldberg syndrome, Weill-Marchesani syndrome as well as autosomal dominant ectopia lentis are also associated with FBN1 pathogenic variants. Offspring of this individual have a 50 percent chance of inheriting the causative variant. References: Attanasio M et al. Dural ectasia and FBN1 mutation screening of 40 patients with Marfan syndrome and related disorders: role of dural ectasia for the diagnosis. Eur J Med Genet. 2013 Jul;56(7):356-60. Collod-Beroud G et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2003 Sep;22(3):199-208. Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Matsukawa R et al. Eight novel mutations of the FBN1 gene found in Japanese patients with Marfan syndrome. Hum Mutat. 2001;17(1):71-2. Ogawa N et al. Evaluating Japanese patients with the Marfan syndrome using high-throughput microarray-based mutational analysis of fibrillin-1 gene. Am J Cardiol. 2011 Dec 15;108(12):1801-7. Wang WJ et al. Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections. J Mol Med (Berl). 2013 Jan;91(1):37-47.
Ambry Genetics RCV000622816 SCV000741017 pathogenic Inborn genetic diseases 2015-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center for Medical Genetics Ghent,University of Ghent RCV000035250 SCV000787253 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000181574 SCV000233877 pathogenic not provided 2018-10-24 criteria provided, single submitter clinical testing The R2220X variant in the FBN1 gene has been published previously in several unrelated patients withMarfan syndrome, and collectively, was not seen in >660 ethnically-matched control alleles(Matsukawa et al., 2001; Comeglio et al., 2007; Ogawa et al., 2011; Attanasio et al., 2013). Inaddition, R2220X was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. R2220X is predicted to cause loss of normal protein function either byprotein truncation or nonsense-mediated mRNA decay. Moreover, multiple other nonsense variants inthe FBN1 gene have been reported in HGMD in association with Marfan syndrome (Stenson et al.,2014).In summary, R2220X in the FBN1 gene is interpreted as a pathogenic variant.
Invitae RCV000701161 SCV000829945 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-06-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2220*) 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 in an individual affected with Marfan syndrome (PMID: 29357934) and has been observed in several individuals with Marfan syndrome (PMID: 11139245, 23684891, 27112580, 17657824, 22772377). ClinVar contains an entry for this variant (Variation ID: 42407). Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035250 SCV000058896 likely pathogenic Marfan syndrome 2012-04-18 criteria provided, single submitter clinical testing The Arg2220X variant (FBN1) has been reported in two Japanese probands with clinical features of Marfan syndrome and was absent in 100 control chromosomes from healthy Japanese individuals (Matsukawa 2001, Ogawa 2011). In addition, this variant has been identified in 1/1090 chromosomes from a broad, though clinically and racially unspecified population (dbSNP rs113001196). This nonsense variant leads to a premature termination codon at position 2220, which is predicted to lead to a truncated or absent protein. Loss of function in the FBN1 gene is an established disease mechanism in Marfan patients. In summary, this variant is likely to be pathogenic, though segregation studies and functional analyses are required to fully establish the pathogenicity of this variant. The clinical significance of this sequence variant should be interpreted in the context of this individual's clinical manifestation.

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