ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.8149G>A (p.Glu2717Lys) (rs187553035)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506463 SCV000603627 likely benign not specified 2016-09-07 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000387643 SCV000787399 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Color RCV000365739 SCV000904472 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-07-22 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the C-terminal region of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 34/246246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Illumina Clinical Services Laboratory,Illumina RCV000362980 SCV000392092 likely benign Ectopia lentis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000270822 SCV000392093 likely benign Acromicric dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000328269 SCV000392094 likely benign MASS syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000365739 SCV000392095 likely benign Thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000273444 SCV000392096 likely benign Stiff skin syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000330801 SCV000392097 likely benign Weill-Marchesani syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000387643 SCV000392098 likely benign Marfan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000295866 SCV000392099 likely benign Geleophysic dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589124 SCV000695619 likely benign not provided 2016-06-28 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.8149G>A (p.Glu2717Lys) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 19/121410 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.0007773 (9/11578). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. This variant has been reported in an affected individual with ascending aortic aneurysm, without strong evidence for causality. Taken together, this variant is classified as Likely benign until more evidence becomes available.
Invitae RCV000229179 SCV000283654 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2717 of the FBN1 protein (p.Glu2717Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs187553035, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant was reported in an individual affected with an ascending aortic aneurysm (PMID: 26188975). ClinVar contains an entry for this variant (Variation ID:237106). 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.

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