ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.2020C>T (p.Arg674Ter) (rs794728403)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223784 SCV000234210 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing The R1014X variant in the KCNH2 gene has been published previously in association with LQTS (Splawski I et al., 2000; Gong Q et al., 2004; Gong Q et al., 2007; Kapplinger J et al., 2009). R1014X was identified in multiple unrelated individuals with LQTS, and was not detected in more than 2,600 reference alleles (Splawski I et al., 2000; Kapplinger J et al., 2009). In addition, R1014X was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth: 5X). Other nonsense variants in the KCNH2 gene have been reported in HGMD in association with LQTS (Stenson et al., 2014). Messenger RNA (mRNA) studies by Gong et al. (2007) demonstrated that the R1014X variant leads to a reduced level of mutant mRNA compared to that of the wild-type allele. The authors concluded that absence of R1014X protein product due to nonsense mediated mRNA decay causes loss of normal protein function (Gong Q et al., 2007).
Invitae RCV000204945 SCV000260318 pathogenic Long QT syndrome 2016-12-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1014 (p.Arg1014*). It is expected to result in an absent or disrupted protein product. Truncating variants in KCNH2 are known to be pathogenic. This particular truncation has been reported in individuals and families affected with severe and mild long QT syndrome (PMID: 10973849, 14642687). ClinVar contains an entry for this variant (Variation ID: 200518). Experimental studies which investigated the functional role of this sequence change using human and animal cell models, have shown that this variant results in the generation of a truncated protein and affects KCNH2 function (PMID: 19324319, 17576861). However, it is not clear if this change also affects trafficking of the protein to the cell membrane (PMID: 19324319, 15572053). In summary, this is a truncating variant which has been shown to affect protein function. For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223784 SCV000280127 pathogenic not provided 2011-03-24 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease

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.