ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.919G>A (p.Val307Met) (rs775192483)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196881 SCV000250670 uncertain significance not provided 2015-04-17 criteria provided, single submitter clinical testing p.Val307Met (V307M) GTG>ATG: c.919 G>A in exon 1 of the SKI gene (NM_003036.3) A variant of unknown significance has been identified in the SKI gene. The V307M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V307M variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The V307M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species, including Methionine which is present as the wild type in several species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, no missense mutations in nearby residues have been reported in association with SKI-related disorders, suggesting 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 TAADV2-1
Invitae RCV000704613 SCV000833568 uncertain significance Shprintzen-Goldberg syndrome 2018-05-02 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 307 of the SKI protein (p.Val307Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs775192483, ExAC 0.006%). This variant has not been reported in the literature in individuals with SKI-related disease. ClinVar contains an entry for this variant (Variation ID: 213686). 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 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.

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