ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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).
Color RCV000772177 SCV000905294 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-04-28 criteria provided, single submitter clinical testing
Invitae RCV000801637 SCV000941421 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2306 of the FBN1 protein (p.Arg2306His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 200097). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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