ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1090C>T (p.Arg364Ter) (rs794728165)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181424 SCV000233726 pathogenic not provided 2017-08-17 criteria provided, single submitter clinical testing The R364X variant in the FBN1 gene has been reported in multiple individuals with Marfan syndrome or incomplete Marfan syndrome (Collod-Beroud et al., 2003; Tjeldhorn et al., 2006; Comeglio et al., 2007; Stheneur et al., 2009). The R364X variant, located in the TGF-beta 1 domain, 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 Human Gene Mutation Database in association with Marfan syndrome or other FBN1-related disorders (Stenson et al., 2014). Furthermore, the R364X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000684777 SCV000544947 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-09-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg364*) 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 reported in the literature in several individuals affected with Marfan syndrome (PMID: 12938084, 17657824, 17663468, 25652356). ClinVar contains an entry for this variant (Variation ID: 199963). Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000619932 SCV000738796 pathogenic Cardiovascular phenotype 2016-05-06 criteria provided, single submitter clinical testing The p.R364* pathogenic mutation (also known as c.1090C>T), located in coding exon 9 of the FBN1 gene, results from a C to T substitution at nucleotide position 1090. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alterationhas been previously describedin multiple patients reported to have classicMarfan syndrome (Rand-HendriksenS et al. Am J Med Genet. 2007;143A(17):1968-77;StheneurC et al.EurJHumGenet. 2009;17(9):1121-8). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000457438 SCV000781328 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000174 SCV001156663 pathogenic not specified 2019-05-25 criteria provided, single submitter clinical testing The FBN1 c.1090C>T; p.Arg364Ter variant (rs794728165) is reported in the literature in multiple individuals affected with suspected Marfan syndrome (Baudhuin 2015, Collod-Beroud 2003, Comeglio 2007, Stheneur 2009, Tan 2017, Tjeldhorn 2006, Weerakkody 2018). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 199963), and is absent from general population databases (Exome Variant Server, 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 to be pathogenic. References: Baudhuin L et al. Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants. J Hum Genet. 2015 60(5):241-52. Collod-Beroud G et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2003 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 28(9):928. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 17(9):1121-8 Tan L et al. FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection. Hum Mol Genet. 2017 Dec 15;26(24):4814-4822. Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006 10(4):258-64. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175536 SCV001339152 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2020-03-11 criteria provided, single submitter clinical testing Variant summary: FBN1 c.1090C>T (p.Arg364X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251536 control chromosomes(gnomAD). c.1090C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g. Collod-Beroud_2003, Weerakkody_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Vascular Biology,Beijing Anzhen Hospital RCV001374819 SCV001439568 likely pathogenic Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000181424 SCV001447091 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000181424 SCV001714516 pathogenic not provided 2019-09-23 criteria provided, single submitter clinical testing PVS1, PS4_moderate, PM2, PP1
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000602307 SCV000731210 pathogenic Familial thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
Center for Medical Genetics Ghent,University of Ghent RCV000457438 SCV000786732 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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