ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs775192483
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Total submissions: 3
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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 2022-09-23 criteria provided, single submitter clinical testing This variant is present in population databases (rs775192483, gnomAD 0.004%). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SKI protein function. ClinVar contains an entry for this variant (Variation ID: 213686). This variant has not been reported in the literature in individuals affected with SKI-related conditions. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 307 of the SKI protein (p.Val307Met).
Ambry Genetics RCV002372174 SCV002687072 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-10-21 criteria provided, single submitter clinical testing The p.V307M variant (also known as c.919G>A), located in coding exon 1 of the SKI gene, results from a G to A substitution at nucleotide position 919. The valine at codon 307 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other 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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