ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1567C>T (p.Arg523Ter) (rs773724817)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203902 SCV000260580 pathogenic Long QT syndrome 2018-06-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 863 (p.Arg863*). It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic. This particular variant has been reported in the literature in several individuals and families affected with long QT syndrome (PMID: 12566525, 14714110, 15840476). In addition, it occurred de-novo in an individual with long QT syndrome (PMID: 22515331). Experimental studies have shown that the truncated protein produced fails to localize to the cell surface and to generate adequate potassium currents (PMID:14714110, 19324319). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000414460 SCV000338933 pathogenic not provided 2016-01-12 criteria provided, single submitter clinical testing
GeneDx RCV000414460 SCV000490553 pathogenic not provided 2017-01-04 criteria provided, single submitter clinical testing The pathogenic R863X variant in the KCNH2 gene has been reported multiple times in association with LQTS (Van Langen et al., 2003; Teng et al., 2004; Nagaoka et al., 2008; Kapa et al., 2009; Zamorano-Leon et al., 2012). Initially, R863X was identified in one European individual diagnosed with LQTS (Van Langen et al., 2003). Additionally, Teng et al. (2004) reported that R863X was present in all six of the clinically affected individuals and was absent from unaffected family members in a four-generation Chinese family with LQTS. In addition, R863X was reportedly found to be de novo in one individual with LQTS and epilepsy with no family history of disease (Zamorano-Leon et al., 2012). Furthermore, the R863X variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server; Exome Aggregation Consortium). Functional studies showed that R863X failed to form functional KCNH2 channels (Teng et al., 2004; Akhavan et al., 2005; Yao et al., 2009). Yu et al. (2014) demonstrated in Hek293 cells transfected with R863X cDNA that, although mRNA levels remained unchanged, this variant caused reduced protein levels and a truncated protein product lacking evidence of proper glycosylation when compared to wild type. The authors suggested this may be the result of defective channel trafficking, inhibition of the glycosylation process and rapid protein degradation in the endoplasmic reticulum (Yu et al., 2014).
Ambry Genetics RCV000624478 SCV000741242 pathogenic Inborn genetic diseases 2015-12-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.