Submissions for variant NM_000138.5(FBN1):c.7754T>C (p.Ile2585Thr)

gnomAD frequency: 0.00002  dbSNP: rs727503054

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150696	SCV000198060	pathogenic	Marfan syndrome	2018-02-14	criteria provided, single submitter	clinical testing	The p.Ile2585Thr variant in FBN1 has been reported in >15 individuals with clini cal features of Marfan syndrome (Liu 1997, Loeys 2001, Biggin 2004, Comeglio 200 7, Howarth 2007, Stheneur 2009, Soylen 2009, Ogawa 2011, Aalberts 2014, Buchan 2 014, Haller 2015, Proost 2015, Yang 2016, Poninska 2016, LMM unpublished data) a nd segregated with disease in 5 affected relatives from two families (Howarth 20 07, Poninska 2016). This variant has also been reported by other clinical labora tories in ClinVar (Variation ID 163462), including a de novo occurrence in one i ndividual referred for Marfan/TAAD testing in one laboratory (SCV000233916.8). I t has been identified in 1/30782 South Asian and 1/33572 Latino chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727503054). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, this v ariant meets criteria to be classified as pathogenic for Marfan syndrome in an a utosomal dominant manner based upon presence in multiple affected individuals, s egregation studies, and de novo occurrence. ACMG/AMP Criteria applied: PS4, PM2, PP1_Moderate, PM6 (Richards 2015).
Blueprint Genetics	RCV000150696	SCV000206957	pathogenic	Marfan syndrome	2015-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000181613	SCV000233916	pathogenic	not provided	2021-12-22	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: 14695540, 17627385, 17657824, 27611364, 31098894, 31211626, 31751304, 32123317, 30739908, 32866347, 10464652, 21907952, 11933199, 24833718, 19293843, 24161884, 26333736, 27146836, 28855619, 27724990, 19159394, 29357934, 30675029, 25907466, 12938084, 12203992, 12203987, 31447099, 33483584, 32679894, 11700157)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524504	SCV000283652	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-31	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 2585 of the FBN1 protein (p.Ile2585Thr). This variant is present in population databases (rs727503054, gnomAD 0.003%). This missense change has been observed in individual(s) with Marfan syndrome and a FBN1-related disease (PMID: 10464652, 11700157, 14695540, 17657824, 19293843, 24833718, 26333736; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 163462). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000766256	SCV000318330	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-11-04	criteria provided, single submitter	clinical testing	The p.I2585T pathogenic mutation (also known as c.7754T>C), located in coding exon 62 of the FBN1 gene, results from a T to C substitution at nucleotide position 7754. The isoleucine at codon 2585 is replaced by threonine, an amino acid with some similar properties, and is located in the cb EGF-like #41 domain. This alteration has been reported in numerous individuals with Marfan syndrome (MFS) and MFS-related phenotypes from a variety of ethnic backgrounds (Loeys B et al. Arch Intern Med. 2001;161(20):2447-2454; Biggin A et al. Hum Mutat. 2004;23(1):99; Soylen B et al. Clin Genet. 2009;75(3):265-270; Yang H et al. Sci Rep, 2016 Sep;6:33002). In one family, six relatives across three generations were reported to have this alteration with clinical features ranging from isolated scoliosis through complete MFS (Poninska JK et al. J Transl Med, 2016 May;14:115). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000181613	SCV000603653	pathogenic	not provided	2021-11-17	criteria provided, single submitter	clinical testing	The FBN1 c.7754T>C; p.Ile2585Thr variant (rs727503054) is reported in the literature in multiple individuals affected with Marfan syndrome (MFS) or MFS-related phenotypes (Becerra-Munoz 2018, Biggin 2004, Collod-Beroud 2003, Comeglio 2007, Fang 2017, Haller 2015, Liu 1997-1998, Loeys 2001, Poninska 2016, Yang 2016). This variant is reported in ClinVar (Variation ID: 163462), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 2585 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious REVEL: 0.642). Based on available information, the p.Ile2585Thr variant is considered to be pathogenic. References: Becerra-Munoz VM et al. The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. Orphanet J Rare Dis. 2018 Jan 22;13(1):16. PubMed: 29357934. Biggin A et al. Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat. 2004 Jan;23(1):99. PMID: 14695540. 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. PMID: 12938084. 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. PMID: 17657824. Fang M et al. Identification of Novel Clinically Relevant Variants in 70 Southern Chinese patients with Thoracic Aortic Aneurysm and Dissection by Next-generation Sequencing. Sci Rep. 2017 Aug 30;7(1):10035. PMID: 28855619. Haller G et al. Genetic Risk for Aortic Aneurysm in Adolescent Idiopathic Scoliosis. J Bone Joint Surg Am. 2015 Sep 2;97(17):1411-7. PMID: 26333736. Liu WO et al. Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders. Genet Test. 1997-1998;1(4):237-42. PMID: 10464652. Loeys B et al. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001 Nov 12;161(20):2447-54. PMID: 11700157 Poninska JK et al. Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations. J Transl Med. 2016 May 4;14(1):115. PMID: 27146836. Yang H et al. Genetic testing of 248 Chinese aortopathy patients using a panel assay. Sci Rep. 2016 Sep 9;6:33002. PMID: 27611364.
Fulgent Genetics, Fulgent Genetics	RCV000515426	SCV000611189	likely 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586322	SCV000695606	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2017-05-12	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.7754T>C (p.Ile2585Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution within a growth factor receptor cysteine-rich domain and a EGF-like calcium-binding domain (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent from the large control database ExAC (0/121220 control chromosomes). In the literature, numerous Marfan syndrome and Marfan syndrome-like patients have been identified as carriers of the variant, and segregation of the allele with disease in families has been observed (Stheneur_EJHG_2009; Howarth_GT_2007), though the allele may not be fully penetrant (Poninska_J Transl Med_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic or pathogenic. Taken together, this variant is classified as pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000150696	SCV000781419	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000150696	SCV000840407	likely pathogenic	Marfan syndrome	2018-02-07	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	RCV000766256	SCV000897674	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-11-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000766256	SCV001332863	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-03-22	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000150696	SCV001433471	pathogenic	Marfan syndrome	2019-04-02	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000181613	SCV001450417	pathogenic	not provided	2018-11-19	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000150696	SCV002025459	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PS4, PS1, PP4
Mayo Clinic Laboratories, Mayo Clinic	RCV000181613	SCV002103256	pathogenic	not provided	2021-09-23	criteria provided, single submitter	clinical testing	PP1_moderate, PP2, PP5, PM2_supporting, PM6, PS4
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000515426	SCV002495772	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	2022-01-18	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in numerous individuals with a clinical diagnosis or features of Marfan syndrome, segregating with disease in at least 2 affected family members, and has also been identified in the de novo state (Selected publications: Loeys 2001 PMID:11700157, Stheneur 2009 PMID:19293843, Haller 2015 PMID:26333736, Fang 2016 PMID:28855619, Poninska 2016 PMID:27146836, Yang 2016 PMID:27611364, Becerra Munoz 2018 PMID:29357934, Damrauer 2019 PMID:31211626, Renner 2019 PMID:30675029, Ferreira de Assis Funari 2020 PMID:31751304, Stark 2020 PMID:32679894). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID:163462). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, this variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000181613	SCV002497779	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000150696	SCV002769130	pathogenic	Marfan syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated EGF-like domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Marfan syndrome or other Marfan syndrome related phenotypes (ClinVar, VCGS, PMID: 11700157). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV003448975	SCV004176723	pathogenic	Connective tissue dysplasia	2023-01-17	criteria provided, single submitter	clinical testing	Heterozygous variant NM_000138:c.7754T>C (p.Ile2585Thr) in FBN1 gene was found on the WES data in female proband (65 y.o., Caucasian) with Connective tissue dysplasia and aortic dissection. This variant has been reported in over 30 articles with variable phenotypes. Clinvar contains entry on this variant (Variation ID: 163462). This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.00001594 (Date of access 17-01-2023). This variant has been reported in over several dozens of studies. In silico predictors are inconsistent in the results (varsome.com). In accordance with ACMG(2015) criteria and Proposal for a Disease- and Gene-Specific Guideline for the Interpretation of Sequenced Variants in the FBN1 Gene for Marfan Syndrome (PMID: 29875124), this variant is classified as Pathogenic with following criteria selected: PS4_Strong, PP5_Strong, PS5, PM2.
All of Us Research Program, National Institutes of Health	RCV000150696	SCV004816738	pathogenic	Marfan syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 2585 in the EGF-like calcium-binding domain of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in many individuals affected with Marfan syndrome (PMID: 19293843, 24161884, 24833718, 25907466, 26333736, 27146836, 31751304, 32679894) and in individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 28855619, 30675029, 30739908, 34498425), including two individuals where the variant was observed to be de novo (PMID: 29357934, 34498425). This variant has been shown to segregate with disease in three families (PMID: 27146836, 27724990, 31751304). In one family, six carriers across three generations showed remarkable variability in clinical features, ranging from isolated scoliosis, aneurysm of the abdominal aorta, thoracic aortic aneurysm and aortic dissection through Marfan syndrome (PMID: 27146836). This variant has been identified in 4/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000181613	SCV005197868	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415147	SCV000492662	pathogenic	Ascending tubular aorta aneurysm; Scoliosis; Tall stature; Joint hypermobility; High myopia; Aortic aneurysm	2016-02-04	no assertion criteria provided	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000150696	SCV000787357	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000181613	SCV001929922	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000181613	SCV001974299	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000150696	SCV004041620	pathogenic	Marfan syndrome	2023-10-09	no assertion criteria provided	clinical testing