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

gnomAD frequency: 0.00001  dbSNP: rs193922228

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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var iant occurred de novo (Katzke 2002, Comeglio 2007, Attanasio 2008, Stheneur 2009 , Soylen 2009, Proost 2015, LMM unpublished data).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	RCV002310995	SCV000320238	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-07-01	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, and is located in the cbEGF-like #35 domain. 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	2023-09-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 10464652, 16342915, 24793577, 17657824, 25907466, 12938084, 18435798, 12203992, 19159394, 27611364, 35058154, 19293843, 31098894, 29848614)
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 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	2017-05-18	criteria provided, single submitter	clinical testing
Invitae	RCV000534047	SCV000627974	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2269 of the FBN1 protein (p.Ile2269Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 10464652, 12203992, 16342915, 18435798, 19159394, 19293843, 25907466, 27611364). ClinVar contains an entry for this variant (Variation ID: 36107). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. 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
CeGaT Center for Human Genetics Tuebingen	RCV000255307	SCV001961507	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000029769	SCV002025420	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
Center for Medical Genetics Ghent, University of Ghent	RCV000029769	SCV000787271	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing