ClinVar Miner

Submissions for variant NM_005751.4(AKAP9):c.4709C>T (p.Ser1570Leu) (rs121908566)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000631713 SCV000752800 uncertain significance Long QT syndrome 2017-11-28 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1570 of the AKAP9 protein (p.Ser1570Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs121908566, ExAC 0.002%). This variant was reported in a long QT family, although family structure was not reported (PMID: 18093912). ClinVar contains an entry for this variant (Variation ID: 5883). Experimental studies have shown that this missense change disrupts bindign between AKAP9 and KCNQ1 (PMID: 18093912). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756981 SCV000884990 uncertain significance not provided 2017-08-07 criteria provided, single submitter clinical testing The p.Ser1570Leu variant has been previously reported in association with long QT syndrome in a single family (Chen 2007). Functional studies performed by Chen et al. suggest the p.Ser1570Leu variant alters the binding between AKAP9 and KCNQ1 which results in a decrease in cyclic AMP associated current in an in vitro model system. This may prolong the action potential of cardiomyocytes but the p.Ser1570Leu variant has not been tested in cardiomyocytes. The serine at position 1570 is weakly conserved and most other non-primate mammalian species have leucine at this position suggesting this change may be evolutionally tolerated. This variant is listed in the genome Aggregation Database (gnomAD) on 2 chromosomes (identified on 2 out of 239,262 chromosomes). Altogether, there is not enough evidence to classify the p.Ser1570Leu variant with certainty.
OMIM RCV000006241 SCV000026423 pathogenic Long QT syndrome 11 2007-12-26 no assertion criteria provided literature only

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