ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1264G>A (p.Ala422Thr)

gnomAD frequency: 0.00002  dbSNP: rs760579911
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196970 SCV000250693 uncertain significance not provided 2025-01-16 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002315620 SCV000739596 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-07-31 criteria provided, single submitter clinical testing The p.A422T variant (also known as c.1264G>A), located in coding exon 4 of the SKI gene, results from a G to A substitution at nucleotide position 1264. The alanine at codon 422 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and threonine 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001048950 SCV001212980 uncertain significance Shprintzen-Goldberg syndrome 2024-10-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 422 of the SKI protein (p.Ala422Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 213707). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SKI protein function with a negative predictive value of 95%. 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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