ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1000C>T (p.Pro334Ser) (rs775433131)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198950 SCV000250674 uncertain significance not provided 2014-05-29 criteria provided, single submitter clinical testing p.Pro334Ser (CCC>TCC): c.1000 C>T in exon 2 of the SKI gene (NM_003036.3 )A variant of unknown significance has been identified in the SKI gene. The P334S variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The P334S 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 P334S 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. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Lastly, no missense mutations in nearby residues have been reported in association with Shprintzen-Goldberg syndrome, indicating that this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD
Invitae RCV000539809 SCV000637270 uncertain significance Shprintzen-Goldberg syndrome 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 334 of the SKI protein (p.Pro334Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs775433131, ExAC 0.009%) but has not been reported in the literature in individuals with a SKI-related disease. ClinVar contains an entry for this variant (Variation ID: 213688). 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 serine 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. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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