ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1480T>A (p.Ser494Thr)

gnomAD frequency: 0.00002  dbSNP: rs781304969
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414146 SCV000492366 uncertain significance not specified 2016-12-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SKI gene. The S494T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S494T variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, although this substitution occurs at a position that is conserved in mammals, S494T is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000460773 SCV000550381 uncertain significance Shprintzen-Goldberg syndrome 2016-08-18 criteria provided, single submitter clinical testing In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SKI-related disease. This sequence change replaces serine with threonine at codon 494 of the SKI protein (p.Ser494Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine.
Ambry Genetics RCV002314118 SCV000739619 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-09-09 criteria provided, single submitter clinical testing The p.S494T variant (also known as c.1480T>A), located in coding exon 5 of the SKI gene, results from a T to A substitution at nucleotide position 1480. The serine at codon 494 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5960 samples (11920 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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