ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1271C>T (p.Pro424Leu) (rs764317955)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486959 SCV000573384 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing The P424L variant in the SKI gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P424L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P424L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P424L as a variant of uncertain significance.
Invitae RCV000537023 SCV000637278 uncertain significance Shprintzen-Goldberg syndrome 2017-03-13 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 424 of the SKI protein (p.Pro424Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs764317955, ExAC 0.006%) but has not been reported in the literature in individuals with a SKI-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but 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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