ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.2174A>C (p.Glu725Ala) (rs747798210)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199766 SCV000250686 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SKI gene. The E725A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 5/8,656 alleles (0.06%) from individuals of African ancestry in large population cohorts (Lek et al., 2016). The E725A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000537625 SCV000637298 uncertain significance Shprintzen-Goldberg syndrome 2017-06-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 725 of the SKI protein (p.Glu725Ala). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. 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 a SKI-related disease. ClinVar contains an entry for this variant (Variation ID: 213700). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on SKI function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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