ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4640C>T (p.Thr1547Ile) (rs183306990)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035207 SCV000058851 uncertain significance not specified 2009-04-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000307321 SCV000392337 likely benign MASS syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000366645 SCV000392338 likely benign Acromicric dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000396472 SCV000392339 likely benign Ectopia lentis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000303714 SCV000392340 likely benign Familial thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000358405 SCV000392341 likely benign Stiff skin syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000268396 SCV000392342 likely benign Marfan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000323350 SCV000392343 likely benign Geleophysic dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000354806 SCV000392344 likely benign Weill-Marchesani syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000559382 SCV000627926 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1547 of the FBN1 protein (p.Thr1547Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs183306990, ExAC 0.02%). This variant has been observed in an individual with clinical features of Marfan syndrome (PMID: 24793577) and in an individual affected with thoracic aortic aneurysm and dissection (PMID: 29543232). ClinVar contains an entry for this variant (Variation ID: 42367). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000268396 SCV000781376 uncertain significance Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000303714 SCV001355732 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-10-08 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 1547 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual with suspected Marfan syndrome (PMID: 24793577) and in an individual with aneurysm of the thoracic aorta (PMID: 29543232). This variant has been identified in 9/282682 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035207 SCV001362385 likely benign not specified 2021-05-10 criteria provided, single submitter clinical testing Variant summary: FBN1 c.4640C>T (p.Thr1547Ile) results in a non-conservative amino acid change located in the a TGF-beta binding (TB) domain (IPR017878) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 152182 control chromosomes, predominantly at a frequency of 0.0024 within the Latino subpopulation in the gnomAD v3 (whole genomes) database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.4640C>T has been reported in the literature in a Latino individual with suspected Marfan Syndrome who was diagnosed based on the old Ghent criteria, however no phenotype details (or co-segregation data) were provided (Lerner-Ellis_ 2014). The variant was also reported in a patient with aortic aneurysm, however this patient also carried a truncating FBN1 variant (FBN1 c.3193delG ,p.Glu1065fsX23) that could explain the phenotype (Weerakkody_2018), thus providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A recent study combining ACMG criteria with FBN1 gene-specific knowledge (i.e. considering critical FBN1 regions and appropriate minor allele frequency (MAF) cutoffs), classified the variant as likely benign (Baudhuin_2019). Four other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV001509492 SCV001716231 uncertain significance not provided 2019-04-15 criteria provided, single submitter clinical testing

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