ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6917G>A (p.Arg2306His) (rs770443276)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000772177 SCV000905294 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-07-15 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the calcium-binding EGF-like motif 40 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 cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 4/246028 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000181583 SCV000233886 likely pathogenic not provided 2014-03-01 criteria provided, single submitter clinical testing p.Arg2306His (CGC>CAC): c.6917 G>A in exon 57 of the FBN1 gene (NM_000138.4) The Arg2306His variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Arg2306His results in a conservative amino acid substitution of one positively charged amino acid with another, the Arg2306 position is well conserved across species. In silico analysis predicts Arg2306His is possibly damaging to the protein structure/function. Mutations in nearby residues (Cys2302Tyr, Cys2307Arg, Cys2307Ser) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Arg2306His was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Arg2306His is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in TAAD panel(s).

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