ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.98A>C (p.Asn33Thr) (rs199473487)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058282 SCV000234226 likely pathogenic not provided 2021-04-29 criteria provided, single submitter clinical testing Reported in association with LQTS (Chen et al., 1999; Splawski et al., 2000; Moss et al., 2002; Shimizu et al., 2009; Mullally et al., 2013); Not observed in large population cohorts (Lek et al., 2016), although it has been reported in 1/187 Caucasian individuals from a control cohort (Ackerman et al., 2003); Published functional studies demonstrate N33T causes defective potassium channel gating in vitro and a repolarization-deficient phenotype in a zebrafish model (Chen et al., 1999; Gianulis et al., 2011; Harley et al., 2012; Jou et al., 2013; Ng et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as likely pathogenic (ClinVar Variant ID# 67553; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 14661677, 22949429, 25417810, 22396785, 21536673, 10973849, 11854117, 23174487, 19926013, 23631430, 10187793, 23303164, 31557540, 19841300, 28087566, 29725305, 32475984)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780363 SCV000917559 likely pathogenic Long QT syndrome 2018-03-13 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.98A>C (p.Asn33Thr) results in a non-conservative amino acid change in the in the PAS domain of the encoded voltage-gated potassium channel that is involved in the regulation of the slow deactivation kinetics (Gianulis 2011). Five of five in-silico tools predict a damaging effect of the variant on protein function. The effect of the variant on protein function was assessed in several in vitro functional studies. KCNH2 dysfunction can occur through a number of mechanisms, including defects in ion permeation, channel opening and closing (gating) or protein trafficking (Gianulis 2011). The variant protein had similar trafficking to the wild type (Harley 2012, Anderson 2014), and also exhibited robust currents when studied in Xenopus oocytes or HEK293 cells. However, the channel deactivation kinetics was significantly accelerated, that might result in prolongation of the ventricular action potential and predispose affected individuals to arrhythmias (Chen 1999, Gianulis 2011). An in vivo functional study performed in a zebrafish model, also supported the pathogenicity of the variant protein by demonstrating a repolarization-deficient phenotype (Jou 2013). Though one study reported the variant to be found in 1/187 Caucasian control individuals, suggesting that it may be a benign polymorphism (Ackerman 2003), the variant allele was not found in large control populations (ExAC and gnomAD) or in healthy controls tested in other studies (Splawski 2000, Lieve 2013). c.98A>C has been reported in the literature in several individuals affected with LQTS (Splawski 2000, Moss 2002, Shimizu 2009, Mullally 2013, Lieve 2013), and also was found in one patient diagnosed with Sudden Cardiac Death (Seidelmann 2017). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000780363 SCV001533773 uncertain significance Long QT syndrome 2020-05-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 33 of the KCNH2 protein (p.Asn33Thr). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with KCNH2-related conditions (PMID: 10973849, 11854117, 23174487, 23631430, 28087566). ClinVar contains an entry for this variant (Variation ID: 67553). This variant has been reported to affect KCNH2 function (PMID: 10187793, 21536673, 23303164, 29725305, 22396785, 25417810) but not to substantially affect trafficking properties in some studies (PMID: 22396785, 25417810). 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058282 SCV000089802 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:10187793;PMID:10973849;PMID:11854117;PMID:14661677;PMID:19841300;PMID:21536673;PMID:22396785).

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