ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.640A>G (p.Ser214Gly) (rs139179843)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200824 SCV000250669 uncertain significance not specified 2016-07-21 criteria provided, single submitter clinical testing The S214G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S214G variant was not observed with any significant frequency in approximately 6400 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 S214G 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, and this substitution occurs at a position where only amino acids with similar properties to Serine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Although S214G has been identified in other individuals referred for Marfan/TAAD genetic testing at GeneDx, the majority of these individuals also harbored a variant in a different gene, which better fit each individuals respective phenotype. A clinical diagnosis of Shprintzen-Goldberg syndrome was not apparent for any of these individuals referred for testing.
Invitae RCV000551275 SCV000637302 uncertain significance Shprintzen-Goldberg syndrome 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 214 of the SKI protein (p.Ser214Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs139179843, ExAC 0.02%) but has not been reported in the literature in individuals with a SKI-related disease. ClinVar contains an entry for this variant (Variation ID: 213685). 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. 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.

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