ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.196T>C (p.Cys66Arg) (rs199473416)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000553516 SCV000627447 uncertain significance Long QT syndrome 2017-08-03 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 66 of the KCNH2 protein (p.Cys66Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNH2-related disease. A different missense substitution at this codon (p.Cys66Gly) has been determined to be pathogenic (PMID: 11854117, 25417810, 10973849, 23303164, 10187793). This suggests that the cysteine residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. This variant identified in the KCNH2 gene is located in the cytoplasmic PAS region of the resulting protein (PMID: 19841300). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change that affects a residue required for adequate protein function, which is suggestive of pathogenicity. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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.