ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6354C>G (p.Ile2118Met) (rs112989722)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156842 SCV000206563 likely pathogenic Marfan syndrome 2014-11-17 criteria provided, single submitter clinical testing The p.Ile2118Met variant in FBN1 has been reported in 1 individual with Marfan s yndrome (Comeglio 2007) and has been identified as a de novo occurrence by our l aboratory in 1 individual with Marfan syndrome. It was absent from large populat ion studies. Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. Additionally, anoth er variant affecting the same nucleotide (p.Ile2118Ile) has been shown to lead t o skipping of exon 51 (Liu 1997), suggesting changes to this nucleotide position may not be tolerated. In summary, although additional studies are required to f ully establish its clinical significance, the p.Ile2118Met variant is likely pat hogenic.
Invitae RCV000530465 SCV000627963 likely pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-04-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 2118 of the FBN1 protein (p.Ile2118Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (rs112989722, ExAC no frequency). This variant has been observed in an individual with Marfan syndrome who met the Ghent criteria (PMID: 17657824). In a ClinVar entry for this variant (Variation ID: 180039), one of the submitters reported having found this variant de novo in a different individual with Marfan syndrome. A different nucleotide substitution at this position (c.6354C>T, p.Ile2118Ile) has been determined to be pathogenic (PMID: 9241263, 16995940, 17224687, 17884807, 18435798, 19720936). This suggests that this nucleotide is critical for FBN1 splicing and that other nucleotide substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781370 SCV000919349 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2017-11-21 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.6354C>G (p.Ile2118Met) variant involves the alteration of a non-conserved nucleotide and 3/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index and p-value, respectively). This variant is absent in 276492 control chromosomes (publication controls and gnomAD). The variant has been reported in 1 individual with Marfan syndrome (Comeglio 2007) and described in ClinVar in a patient with Marfan syndrome as a de novo event. Another variant affecting the same nucleotide, c.6354C>T (p.Ile2118Ile - scored DV by LCA) has been reported and found to cause skipping of exon 52 (PMID: 9241263), 3/5 splicing prediction tools for the variant of interest do predict an impact on splicing. However, these predictions have not been functionally assessed. In addition, a clinical diagnostic laboratory has classified the variant as "likely pathogenic." Taken together, this variant is classified as likely pathogenic.

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