ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1162G>A (p.Ala388Thr) (rs376736872)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197343 SCV000250650 uncertain significance not provided 2015-12-29 criteria provided, single submitter clinical testing The A388T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has been seen in one other individual referred for Marfan/TAAD genetic testing at GeneDx. The A388T variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the A388T 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. Nevertheless, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000638889 SCV000760443 uncertain significance Shprintzen-Goldberg syndrome 2017-12-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 388 of the SKI protein (p.Ala388Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs376736872, ExAC 0.003%). This variant has not been reported in the literature in individuals with SKI-related disease. ClinVar contains an entry for this variant (Variation ID: 213667). 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 and their clinical significance is uncertain. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000197343 SCV001147106 uncertain significance not provided 2018-02-01 criteria provided, single submitter clinical testing

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