ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1910_1912AGA[1] (p.Lys638del) (rs794728442)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181980 SCV000234283 likely pathogenic not provided 2017-01-03 criteria provided, single submitter clinical testing The c.1913_1915delAGA variant in the KCNH2 gene has been previously reported in association with LQTS (Splawski et al., 2000; Kapplinger et al., 2009), and was absent from approximately 2,600 control alleles (Kapplinger et al., 2009). Furthermore, the c.1913_1915delAGA 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. Located in the S6 segment of the KCNH2 gene, pathogenic variants in this region are expected to disrupt potassium transport (Splawski et al., 2000).Therefore, this variant is likely pathogenic
Invitae RCV000456814 SCV000543450 likely pathogenic Long QT syndrome 2016-09-11 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 7 of the KCNH2 mRNA (c.1913_1915delAGA). This leads to the deletion of 1 amino acid residue in the KCNH2 protein (p.Lys638del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (rs794728442, ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome (PMID: 10973849, Invitae database) and has been shown to segregate with the phenotype in a multigenerational family (PMID: 26831020). ClinVar contains an entry for this variant (Variation ID: 200646). Different missense substitutions at this codon (p.Lys638Glu and p.Lys638Asn) have been determined to be important for protein trafficking (PMID: 25417810). This suggests that a lysine residue at this position is necessary for normal KCNH2 protein function. This variant identified in the KCNH2 gene is located in the transmembrane spanning pore/S6 region of the resulting protein (PMID: 19841300, 25348405). In summary, this variant is absent from population databases, has been observed in several unrelated individuals with long QT syndrome, and affects an amino acid that is involved in protein trafficking. In the absence of additional information, at this time this variant has been classified as Likely Pathogenic.

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.