ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.167G>T (p.Arg56Leu) (rs199472845)

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 RCV000181931 SCV000234234 pathogenic not provided 2014-07-07 criteria provided, single submitter clinical testing p.Arg56Leu (CGG>CTG): c.167 G>T in exon 2 of the KCNH2 gene (NM_000238.2)While the R56L variant in the KCNH2 gene has not been reported to our knowledge, a mutation affecting this same residue, (R56Q), has been reported in association with LQTS (Chen et al., 1999). Additionally, mutations in nearby residues (G53V, Y54H, S55L, A57P, E58K) have been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein. R56L results in a non-conservative amino acid substitution of Arginine at a position that is conserved across species. In silico analysis predicts R56L is probably damaging to the protein structure/function. Furthermore, R56L 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.In summary, R56L in the KCNH2 gene is interpreted as a likely disease-causing mutation. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000461590 SCV000543465 uncertain significance Long QT syndrome 2017-09-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 56 of the KCNH2 protein (p.Arg56Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 200557). 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. A different missense substitution at this codon (p.Arg56Gln) has been determined to be pathogenic (PMID: 10187793, 10973849, 11854117, 15475579, 20876384, 21536673, 25008322,25809256, 25923442). This suggests that the arginine residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. 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: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function that resides in a residue important for protein function. However genetic data is insufficient to classify it conclusively. 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.