ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058282 SCV000234226 likely pathogenic not provided 2016-12-30 criteria provided, single submitter clinical testing The N33T variant in the KCNH2 gene has been published previously in association with LQTS and also as a benign polymorphism (Chen et al.,1999; Splawski et al., 2000; Ackerman et al., 2003; Shimizu et al., 2009). Chen et al. (1999) reported that N33T, located in the N-terminus of KCNH2, slowed the activation of the KCNH2 channel (Chen et al.,1999). Shimizu et al. (2009) detected N33T in three subjects with LQTS. Splawski et al. (2000) reported N33T to be present in two families with LQTS and did not detect the variant in more than 400 control chromosomes (Splawski et al., 2000). The N33T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, Ackerman et al. (2003) reported N33T in KCNH2 to be present in one out of 187 Caucasian control individuals (0.5%), suggesting it may be a benign polymorphism (Ackerman et al., 2003).Three recent functional studies confirmed that N33T causes defective potassium channel gating in vitro (Gianulis et al., 2011; Harley et al., 2012., Jou et al., 2013). Gianulis et al. (2011) noted that variants located on one face of the PAS domain, including N33T, resulted in less steady-state inactivation and faster deactivation kinetics. Findings from Harley et al. (2012) suggest that N33T results in LQT2 due to the direct malfunction of the channel in the membrane (Harley et al., 2012). Finally, Jou et al. (2013) performed an in vivo functional assay in a zebrafish model, which supported the pathogenicity of N33T by displaying a repolarization-deficient phenotype.N33T in KCNH2 is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Variants affecting nearby residues (I30T, I31S, I31T, A32T, R35W) have been reported in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein.Therefore, this variant is likely pathogenic).
Integrated Genetics/Laboratory Corporation of America 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.
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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