ClinVar Miner

Submissions for variant NM_003036.4(SKI):c.1070G>A (p.Arg357Gln) (rs200874294)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000542904 SCV000894749 uncertain significance Shprintzen-Goldberg syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000195711 SCV000250675 uncertain significance not specified 2017-05-24 criteria provided, single submitter clinical testing p.Arg357Gln (CGG>CAG): c.1070 G>A in exon 2 of the SKI gene (NM_003036.3) Mutations in the SKI gene have been reported in association with Shprintzen-Goldberg syndrome (SGS). SGS is a rare autosomal dominant disorder characterized by craniofacial, skeletal, neurological and cardiovascular anomalies. Cardiovascular anomalies of SGS include mitral valve prolapse and aortic root dilatation. Mutations in SKI usually occur de novo in the affected individual and are not inherited from an affected parent (Greally M, 2013; Carmignac et al., 2012, Doyle et al 2012) .A variant of unknown significance has been identified in the SKI gene. The R357Q variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The R357Q variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R357Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Nevertheless, in silico algorithms are not consistent in their predictions but at least two concur that R357Q is benign to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with TAAD, suggesting 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 TAAD
Invitae RCV000542904 SCV000637273 uncertain significance Shprintzen-Goldberg syndrome 2018-02-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 357 of the SKI protein (p.Arg357Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs200874294, ExAC 0.006%). ClinVar contains an entry for this variant (Variation ID: 213689). This variant has not been reported in the literature in individuals with SKI-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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