ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1841G>A (p.Arg614His) (rs772977598)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000552830 SCV000627470 uncertain significance Long QT syndrome 2017-03-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 954 of the KCNH2 protein (p.Arg954His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. While this variant is not present in population databases (rs772977598), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been identified in an individual affected with long QT syndrome (PMID: 27026747). This variant identified in the KCNH2 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000772104 SCV000905140 uncertain significance Arrhythmia 2018-09-16 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been identified in an individual affected with long QT syndrome (PMID: 27026747). This variant has also been identified in 4/220552 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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