ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1117C>T (p.Arg373Cys)

gnomAD frequency: 0.00001  dbSNP: rs749507746
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000465525 SCV000550373 uncertain significance Shprintzen-Goldberg syndrome 2024-06-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the SKI protein (p.Arg373Cys). This variant is present in population databases (rs749507746, gnomAD 0.004%). This missense change has been observed in individual(s) with thoracic aortic aneurysm (PMID: 33824467). ClinVar contains an entry for this variant (Variation ID: 409970). 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 expected to disrupt SKI protein function with a positive 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.
Department of Vascular Biology, Beijing Anzhen Hospital RCV001374770 SCV001439487 uncertain significance Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research
CeGaT Center for Human Genetics Tuebingen RCV001532046 SCV001747426 uncertain significance not provided 2021-03-01 criteria provided, single submitter clinical testing
GeneDx RCV001532046 SCV001791912 uncertain significance not provided 2023-08-07 criteria provided, single submitter clinical testing Has been reported as a variant of uncertain significance in a Chinese patient with TAAD (Li et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33824467)
Ambry Genetics RCV002436441 SCV002750423 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-10-18 criteria provided, single submitter clinical testing The p.R373C variant (also known as c.1117C>T), located in coding exon 3 of the SKI gene, results from a C to T substitution at nucleotide position 1117. The arginine at codon 373 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in an isolated thoracic aortic aneurysm and dissections cohort, but clinical details were limited (Li Y et al. Eur J Hum Genet, 2021 Jul;29:1129-1138). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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