ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1247C>T (p.Ala416Val)

gnomAD frequency: 0.00001  dbSNP: rs775044622
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197794 SCV000250679 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing p.Ala416Val (GCG>GTG): c.1247 C>T in exon 4 of the SKI gene (NM_003036.3) A variant of unknown significance has been identified in the SKI gene. The A416V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A416V variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across vertebrates. Moreover, in silico analysis predicts that this variant is likely damaging to the protein structure/function. Nevertheless, the A416V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, no missense mutations in nearby residues have been reported, 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 TAADV2-1
Invitae RCV001206777 SCV001378103 uncertain significance Shprintzen-Goldberg syndrome 2022-07-11 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 213693). This variant has not been reported in the literature in individuals affected with SKI-related conditions. This variant is present in population databases (rs775044622, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 416 of the SKI protein (p.Ala416Val).
Ambry Genetics RCV003362721 SCV004053803 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-09-13 criteria provided, single submitter clinical testing The p.A416V variant (also known as c.1247C>T), located in coding exon 4 of the SKI gene, results from a C to T substitution at nucleotide position 1247. The alanine at codon 416 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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