ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1309G>A (p.Ala437Thr) (rs544709718)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000251995 SCV000319389 benign Cardiovascular phenotype 2019-06-20 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification;Other data supporting benign classification
Invitae RCV000474123 SCV000550377 uncertain significance Shprintzen-Goldberg syndrome 2018-05-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 437 of the SKI protein (p.Ala437Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs544709718, ExAC 0.04%) 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 output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine 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. 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. 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.
GeneDx RCV000520591 SCV000620001 uncertain significance not specified 2017-08-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SKI gene. The A437T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 24/58,564 alleles from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The A437T 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. However, this substitution occurs at a position that is not conserved across species and threonine (T) is tolerated at this position in multiple species. Moreover, in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with SKI-related disorders (Stenson et al., 2014).
Fulgent Genetics,Fulgent Genetics RCV000474123 SCV000894750 uncertain significance Shprintzen-Goldberg syndrome 2018-10-31 criteria provided, single submitter clinical testing

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