Submissions for variant NM_003036.4(SKI):c.464C>G (p.Ala155Gly)

gnomAD frequency: 0.00001  dbSNP: rs559020511

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000461900	SCV000550384	uncertain significance	Shprintzen-Goldberg syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 155 of the SKI protein (p.Ala155Gly). This variant is present in population databases (rs559020511, gnomAD 0.008%). 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: 373594). 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.
Fulgent Genetics, Fulgent Genetics	RCV000461900	SCV000896266	uncertain significance	Shprintzen-Goldberg syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002338974	SCV002635318	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-11-19	criteria provided, single submitter	clinical testing	The p.A155G variant (also known as c.464C>G), located in coding exon 1 of the SKI gene, results from a C to G substitution at nucleotide position 464. The alanine at codon 155 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. 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.
GeneDx	RCV002510883	SCV002820695	uncertain significance	not provided	2023-01-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
GeneDx	RCV000413541	SCV000492202	uncertain significance	not specified	2016-11-29	flagged submission	clinical testing	A variant of uncertain significance has been identified in the SKI gene. The A155G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 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, the A155G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nonetheless, this substitution occurs at a position that is conserved across species, and two of three in silico programs predict this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.