ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.934C>T (p.Arg312Cys) (rs199472885)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171561 SCV000050607 uncertain significance Long QT syndrome 2018-04-05 criteria provided, single submitter research
Invitae RCV000171561 SCV000283990 uncertain significance Long QT syndrome 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 312 of the KCNH2 protein (p.Arg312Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199472885, ExAC 0.02%). This variant has been observed in an individual affected with long QT syndrome and in an individual who presented with sinus bradycardia, first-degree atrioventricular block, moderate mitral regurgitation and impaired left ventricular relaxation on ECHO, and who had a family history of sudden death (PMID: 10973849, 23861362). ClinVar contains an entry for this variant (Variation ID: 67547). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics,Fulgent Genetics RCV000515393 SCV000611203 pathogenic Short QT syndrome 1; Long QT syndrome 2 2017-05-18 criteria provided, single submitter clinical testing
Color RCV001192113 SCV001360089 uncertain significance Arrhythmia 2019-07-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001255552 SCV001432023 uncertain significance not specified 2020-08-25 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.934C>T (p.Arg312Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250256 control chromosomes, predominantly at a frequency of 0.00058 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Long QT Syndrome phenotype (0.00012), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.934C>T has been reported in the literature in and individual with sinus bradycardia, first-degree atrioventricular block, moderate mitral regurgitation, and impaired left ventricular relaxation on ECHO (Ng_2013), in an infant with isolated isolated bi-ventricular non-compaction presented with restrictive hemodynamics (Miura_2019) and in several individuals with Long QT syndrome (e.g. Splawski_2000, Song_2018, Shimizu_2009, Kapplinger_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058276 SCV000089796 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:10973849;PMID:15051636;PMID:19716085). 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.