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

gnomAD frequency: 0.00001  dbSNP: rs775044622

Total submissions: 3

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001206777	SCV001378103	uncertain significance	Shprintzen-Goldberg syndrome	2024-08-08	criteria provided, single submitter	clinical testing	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). This variant is present in population databases (rs775044622, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SKI-related conditions. ClinVar contains an entry for this variant (Variation ID: 213693). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SKI protein function. 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.
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, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.