ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.2843G>A (p.Arg948His) (rs199473011)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182047 SCV000234350 pathogenic not provided 2011-10-18 criteria provided, single submitter clinical testing The Arg948His mutation in the KCNH2 gene has been published previously in a single individual from a cohort of Japanese patients with LQTS, and was not detected in 400 control alleles from the same population. Other amino acid substitutions affecting the same codon (Arg948Ser, Arg948Cys) and nearby codons (Ser937Asn, Leu955Val) have also been reported in association with LQTS, further supporting the functional importance of this position and this region of the protein. In addition, Arg948His was not detected in 308 control alleles from individuals of various ethnic backgrounds tested at GeneDx, indicating it is not a common benign variant in these populations. In summary, the presence of Arg948His in the KCNH2 gene is consistent with a diagnosis of LQTS. The variant is found in LQT panel(s).
Institute of Human Genetics, Klinikum rechts der Isar RCV000578446 SCV000680268 likely pathogenic Long QT syndrome 2 2017-12-09 criteria provided, single submitter clinical testing
Invitae RCV000794762 SCV000934189 uncertain significance Long QT syndrome 2020-05-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 948 of the KCNH2 protein (p.Arg948His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199473011, ExAC 0.1%). This variant has been observed in an individual affected with long QT syndrome (PMID: 20541041). ClinVar contains an entry for this variant (Variation ID: 67443). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The observation of one or more missense substitutions at this codon (p.Arg948Ser) in an affected individual suggests that this may be a clinically significant residue (PMID: 20541041). 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.
Mendelics RCV000578446 SCV001137542 uncertain significance Long QT syndrome 2 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV001191828 SCV001359740 uncertain significance Arrhythmia 2019-09-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001358716 SCV001554551 uncertain significance not specified 2021-03-18 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.2843G>A (p.Arg948His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 165946 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2843G>A has been reported in the literature in individuals/families affected with Long QT Syndrome (e.g. Itoh_2010, Itoh_2016, Pottinger_2020), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058170 SCV000089690 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:20541041). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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.