Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000058282 | SCV000234226 | likely pathogenic | not provided | 2024-07-02 | criteria provided, single submitter | clinical testing | Reported in association with LQTS and sudden cardiac death (PMID: 10187793, 11854117, 19926013, 23174487, 28087566, 10973849); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate p.(N33T) causes defective potassium channel gating in vitro and a repolarization-deficient phenotype in a zebrafish model (PMID: 10187793, 21536673, 22396785, 31557540, 23303164, 26958806); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14661677, 22949429, 25417810, 22396785, 21536673, 11854117, 23174487, 19926013, 23631430, 10187793, 31557540, 19841300, 28087566, 29725305, 32475984, BayeJ2022, 10973849, 34801551, 23303164, 37187232, 35688148, 26958806) |
Women's Health and 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. |
Labcorp Genetics |
RCV000780363 | SCV001533773 | uncertain significance | Long QT syndrome | 2023-08-15 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with KCNH2-related conditions (PMID: 10973849, 11854117, 23174487, 23631430, 28087566). 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 10187793, 21536673, 22396785, 23303164, 25417810, 29725305, 31557540). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 67553). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 33 of the KCNH2 protein (p.Asn33Thr). |
Ambry Genetics | RCV003343627 | SCV004074761 | uncertain significance | Cardiovascular phenotype | 2023-07-17 | criteria provided, single submitter | clinical testing | The p.N33T variant (also known as c.98A>C), located in coding exon 2 of the KCNH2 gene, results from an A to C substitution at nucleotide position 98. The asparagine at codon 33 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in long QT syndrome and sudden cardiac death cohorts (Splawski I et al. Circulation, 2000 Sep;102:1178-85; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10:). This alteration has also been reported in control cohorts (Ackerman MJ et al. Mayo Clin Proc, 2003 Dec;78:1479-87; Kapa S et al. Circulation, 2009 Nov;120:1752-60). This variant has been studied in numerous functional settings with a possible impact on protein function (Gianulis EC et al. J Biol Chem, 2011 Jun;286:22160-9; Jou CJ et al. Circ Res, 2013 Mar;112:826-30; Perry MD et al. J Physiol, 2016 Jul;594:4031-49; Ng CA et al. Heart Rhythm, 2020 Mar;17:492-500). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
All of Us Research Program, |
RCV000780363 | SCV005426275 | likely pathogenic | Long QT syndrome | 2024-05-30 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with threonine at codon 33 in the N-terminal PAS domain of the KCNH2 protein. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have not conclusively demonstrated mechanism of disease of this variant but generally indicate that this variant results in the altered kinetics of the potassium channel activity and reduced protein expression (PMID: 10187793, 22396785, 23303164, 26958806, 29725305, 31557540, 34801551). This variant has been reported in over ten individuals affected with long QT syndrome (PMID: 10973849, 11854117, 19926013, 23174487, 23631430), in an individual with sudden cardiac death (PMID: 28087566), and in a few unaffected individuals (PMID: 14661677, 19841300, 22949429). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
Cardiovascular Biomedical Research Unit, |
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). |