ClinVar Miner

Submissions for variant NM_005751.4(AKAP9):c.5048C>T (p.Thr1683Met) (rs146305558)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231836 SCV000289093 uncertain significance Long QT syndrome 2016-05-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1683 of the AKAP9 protein (p.Thr1683Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs146305558, ExAC 0.05%). This variant been reported in individuals affected by sudden infant death syndrome (PMID: 26350513). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000255316 SCV000321390 uncertain significance not provided 2016-06-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the AKAP9 gene. The T1683M variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This 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, in the 1000 Genomes Project, or in the Exome Aggregation Consortium (ExAC). The T1683M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign
Fulgent Genetics,Fulgent Genetics RCV000764727 SCV000895862 uncertain significance Long QT syndrome 11 2018-10-31 criteria provided, single submitter clinical testing

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