ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1687G>A (p.Gly563Arg) (rs199473669)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767043 SCV000234186 uncertain significance not provided 2017-12-08 criteria provided, single submitter clinical testing The G903R variant of uncertain significance has been identified in the KCNH2 gene. This variant has previously been published in association with LQTS and sudden unexplained death (Kapplinger et al., 2009; Cann et al., 2016). Cann et al. (2016) reported G903R in a patient with sudden unexplained death who was noted to have a viral infection and a normal heart on autopsy, and was also identified in a relative with a prolonged QTc interval (Cann et al., 2016). This variant is observed in 12/58,764 alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The G903R 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000181883 SCV000539431 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in 3 patients referred for LQTS genetic testing. The variant is not in ExAC. It is classified with 1 star in ClinVar as VUS by GeneDx.
Invitae RCV000465531 SCV000543411 uncertain significance Long QT syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 903 of the KCNH2 protein (p.Gly903Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with long QT syndrome or Brugada syndrome (PMID: 27000522, 19716085, Invitae). ClinVar contains an entry for this variant (Variation ID: 67428). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000621231 SCV000738121 uncertain significance Cardiovascular phenotype 2017-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000777704 SCV000913647 uncertain significance Arrhythmia 2018-08-13 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 reported in three individuals referred for long QT syndrome genetic testing (PMID: 19716085). This variant has also been identified in 18/152292 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058153 SCV000089673 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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