ClinVar Miner

Submissions for variant NM_005585.5(SMAD6):c.1184A>G (p.Lys395Arg) (rs149949971)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000546579 SCV000650577 uncertain significance Aortic valve disease 2 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 395 of the SMAD6 protein (p.Lys395Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs149949971, ExAC 0.1%) but has not been reported in the literature in individuals with a SMAD6-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but these predictions have not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. However, this sequence change has uncertain impact on splicing. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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