ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7048A>G (p.Ile2350Val) (rs794728263)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181587 SCV000233890 uncertain significance not provided 2014-01-12 criteria provided, single submitter clinical testing p.Ile2350Val (ATC>GTC): c.7048 A>G in exon 58 of the FBN1 gene (NM_000138.4)The I2350V variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The I2350V variant is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. The I2350 residue is conserved through mammals in evolution. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function.. Nevertheless, the I2350V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.With the clinical and molecular information available at this time, we cannot definitively determine if I2350V is a disease-causing mutation or a rare benign variant.The variant is found in TAAD panel(s).
Invitae RCV000469404 SCV000544871 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2016-08-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2350 of the FBN1 protein (p.Ile2350Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 200101). 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. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000584375 SCV000692229 uncertain significance Loeys-Dietz syndrome 2017-03-30 no assertion criteria provided clinical testing

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