ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1738C>G (p.Arg580Gly) (rs199473438)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181889 SCV000234192 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNH2 gene. The R920G variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in other individuals referred for arrhythmia genetic testing at GeneDx, although no informative segregation data are available to further clarify the role of this variant in disease. This variant is also not observed in large population cohorts (Lek et al., 2016). The R920G 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, although other missense variants at the same residue (R920Q, R920W) have also been reported in association with LQTS (Kapplinger et al., 2009), the clinical significance of these variants also remains to be definitively determined.
Invitae RCV000631667 SCV000752750 uncertain significance Long QT syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 920 of the KCNH2 protein (p.Arg920Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This sequence change has not been published in the literature and is not present in population databases. 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 (SIFT, Mutation Taster, Align-GVGD) all suggest that this sequence change is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a novel missense change. Although there is no indication that this sequence change affects protein function or causes disease, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000778036 SCV000914149 uncertain significance Arrhythmia 2018-05-30 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant 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 nor has the variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 1/120540 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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