ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.104C>G (p.Pro35Arg) (rs397514589)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475694 SCV000550383 uncertain significance Shprintzen-Goldberg syndrome 2016-09-23 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 35 of the SKI protein (p.Pro35Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual 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"). Two different missense substitutions at this codon (p.Pro35Ser and p.Pro35Gln) have been determined to be pathogenic (PMID: 23023332, 23103230). This suggests that the proline residue is critical for SKI protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a novel missense change with uncertain impact on protein function. While it is absent from the population and affects an important residue, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago RCV000475694 SCV000597058 likely pathogenic Shprintzen-Goldberg syndrome 2016-09-21 criteria provided, single submitter clinical testing

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