ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1420C>G (p.Pro474Ala)

gnomAD frequency: 0.00001  dbSNP: rs1057518494
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413715 SCV000492188 uncertain significance not specified 2016-12-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SKI gene. The P474A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P474A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P474A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV003517188 SCV004314909 uncertain significance Shprintzen-Goldberg syndrome 2023-05-30 criteria provided, single submitter clinical testing Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SKI protein function. ClinVar contains an entry for this variant (Variation ID: 373583). This variant has not been reported in the literature in individuals affected with SKI-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 474 of the SKI protein (p.Pro474Ala). 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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