ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.6806T>C (p.Ile2269Thr) (rs193922228)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000029769 SCV000058900 pathogenic Marfan syndrome 2016-01-26 criteria provided, single submitter clinical testing The p.Ile2269Thr variant in FBN1 has been reported in 9 individuals with Marfan syndrome or features of Marfan syndrome, including 2 individuals in whom the var iant occurred de novo (Katzke 2002, Comeglio 2007, Attanasio 2008, Stheneur 2009 , Soylen 2009, Proost 2015, LMM unpublished data). This variant was absent from large population studies. Computational prediction tools and conservation analys is suggest that this variant may impact the protein. In summary, the p.Ile2269Th r variant meets our criteria to be classified as pathogenic for Marfan syndrome in an autosomal dominant manner based upon presence in affected individuals, abs ence from controls and de novo occurrences.
Ambry Genetics RCV000246714 SCV000320238 pathogenic Cardiovascular phenotype 2018-07-03 criteria provided, single submitter clinical testing The p.I2269T pathogenic mutation (also known as c.6806T>C), located in coding exon 55 of the FBN1 gene, results from a T to C substitution at nucleotide position 6806. The isoleucine at codon 2269 is replaced by threonine, an amino acid with similar properties. This variant has been detected in multiple individuals with a clinical diagnosis of Marfan syndrome (MFS) and was reported to be de novo in two of the probands (Katzke S et al, Hum. Mutat. 2002; 20(3):197-208; Attanasio M et al, Clin. Genet. 2008l; 74(1):39-46; Söylen B et al, Clin. Genet. 2009; 75(3):265-70; Stheneur C et al. Eur. J. Hum. Genet. 2009;17:1121-8; Proost D et al. Hum. Mutat. 2015;36:808-14). This variant has also been identified in several cohorts with aortic or connective tissue disease (Liu WO et al, Genet. 1997/98; 1(4):237-42; Comeglio P et al. Hum. Mutat. 2007;28:928; Yang H et al. Sci Rep. 2016;6:33002). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000255307 SCV000322364 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing The I2269T pathogenic variant in the FBN1 gene has been reported in multiple individuals with Marfan syndrome or features of Marfan syndrome, and was collectively absent from >900 reference alleles (Liu et al., 1997; Katzke et al., 2002; Comeglio et al., 2007; Attanasio et al., 2008; Stheneur et al., 2009; Söylen et al., 2009; Proost et al., 2015). In addition, I2269T was reported as de novo in two unrelated French individuals with Marfan syndrome by Stheneur et al. (2009). I2269T results in a non-conservative amino acid substitution within the calcium-binding EGF-like domain at a position that is conserved across species. Consequently, in silico analyses predicts this variant is probably damaging to the protein structure/function. Furthermore, the I2269T 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, I2269T in the FBN1 gene is interpreted as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000255307 SCV000603655 likely pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing The c.6806T>C; p.Ile2269Thr variant (rs193922228) has been reported in multiple individuals affected with Marfan syndrome or FBN1-related disorders (Attanasio 2008, Comeglio 2007, Katzke 2002, Liu 1997, Proost 2015, Soylen 2009, Stheneur 2009), and is classified as pathogenic/likely pathogenic in ClinVar (variant ID 36107). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism). The isoleucine at codon 2269 is a highly conserved residue located within the calcium-binding EGF-like domain. Based on the above information, this variant is likely to be pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515227 SCV000611193 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 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000534047 SCV000627974 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-05-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2269 of the FBN1 protein (p.Ile2269Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals affected with Marfan syndrome (PMID: 10464652, 12203992, 16342915 , 18435798, 19159394, 19293843, 25907466, 27611364). ClinVar contains an entry for this variant (Variation ID: 36107). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). However, the clinical significance of these predictions is uncertain. In summary, this is a rare missense change that is absent from the normal population and has been reported in numerous affected individuals. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586646 SCV000695589 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2017-03-01 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.6806T>C (p.Ile2269Thr) variant involves the missense alteration of a conserved nucleotide. The variant falls within a highly conserved EGF-like calcium binding domain #35 and 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in the large control population ExAC (0/121388 control chromosomes). Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic or pathogenic, and numerous publications in the literature have reported the variant in affected individuals, including 2 cases where patients had the variant as a de novo mutational event. Taken together, this variant is classified as pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000029769 SCV000781404 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000029769 SCV000787271 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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