ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1582C>T (p.Arg528Trp) (rs864622403)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206797 SCV000260492 uncertain significance Long QT syndrome 2015-09-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 528 of the KCNH2 protein (p.Arg528Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases and has not been reported in the literature. In an experimental study using an animal cell model, this missense change was shown to slow deactivation of the potassium channel (PMID: 16166152). In summary, this is a novel missense change that has been shown to affect protein function. However, there is no data to show segregation with disease . Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000772064 SCV000905093 uncertain significance Arrhythmia 2018-10-30 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain S4 of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental functional study has shown that this variant decreases the rate of deactivation and and increase the rate of activation of the potassium channel (PMID: 16166152). However, clinical significance of this finding is not clear. To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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