ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7754T>C (p.Ile2585Thr) (rs727503054)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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2009, Soylen 2009, Ogawa 2011, Aalberts 2014, Buchan 2 014, Haller 2015, Proost 2015, Yang 2016, Poninska 2016, LMM unpublished data) a nd segregated with disease in 5 affected relatives from two families (Howarth 20 07, Poninska 2016).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 2018-04-24 criteria provided, single submitter clinical testing The I2585T pathogenic variant in the FBN1 gene has been reported previously in association with Marfan syndrome(Loeys et al., 2001; Howarth et al., 2007; Stheneur et al., 2009; Aalberts et al., 2014). Loeys et al. (2001) reportedI2585T in a 16 year-old patient with skeletal and cardiovascular features consistent with a Marfan-like disorder, and ina 21 year-old unrelated patient with skeletal, cardiovascular, and ocular features consistent with classic Marfansyndrome. In both cases the variant was reported to have occurred de novo. In addition, I2585T has been observed inmultiple unrelated individuals referred for Marfan/TAAD genetic testing at GeneDx, with presumed de novo occurrence in at least one affected individual. This variant segregated with features of Marfan syndrome in multiple unrelated families, though variable expressivity was observed (Howarth et al., 2007; Poninska et al., 2016; internal unpublished data). In addition, the I2585T variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016). I2585T results in a non-conservative amino acid substitution at a position where only amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this substitution to be damaging to protein structure/function. Finally, the I2585T variant lies within a calcium-binding EGF-like domain of the FBN1 gene and other nearby missense variants (G2586W, R2589G) are reported in association with Marfan syndrome or thoracic aortic aneurysm/dissection (Collod-Beroud et al., 2003; Stenson et al., 2014).
Invitae RCV000524504 SCV000283652 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2585 of the FBN1 protein (p.Ile2585Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (rs727503054, ExAC no frequency). This variant has been reported in multiple individuals affected with Marfan syndrome (PMID: 10464652, 14695540, 17657824, 19293843, 24833718, 11700157, 26333736). This variant has been observed to be de novo in an individual with a FBN1-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 163462). 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: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000252885 SCV000318330 pathogenic Cardiovascular phenotype 2019-09-16 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (benign);Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;Other strong data supporting pathogenic classification
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506823 SCV000603653 pathogenic not specified 2018-12-19 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 as pathogenic/likely pathogenic by multiple laboratories 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 (SIFT, PolyPhen-2) predict that this variant is tolerated. 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. 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. 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. 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. 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. 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. 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. 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. Yang H et al. Genetic testing of 248 Chinese aortopathy patients using a panel assay. Sci Rep. 2016 Sep 9;6:33002.
Fulgent Genetics,Fulgent Genetics RCV000515426 SCV000611189 likely 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
Integrated Genetics/Laboratory Corporation of America 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 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 Thoracic aortic aneurysm and aortic dissection 2018-11-20 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415147 SCV000492662 pathogenic Dilatation of ascending aorta; Scoliosis; Tall stature; Joint hypermobility; Severe 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

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