ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1235G>A (p.Arg412Gln) (rs199472794)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182207 SCV000234510 uncertain significance not provided 2015-12-07 criteria provided, single submitter clinical testing The R539Q variant in the KCNQ1 gene has been reported previously in one individual referred for LQTS genetic testing, and this variant was absent from more than 2,600 control alleles (Kapplinger J et al., 2009). In addition, the NHLBI Exome Sequencing project reports R539Q was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Another missense variant affecting the same residue (R539W) and variants in nearby residues (R533W, V541I, E543K, S546L, Q547R), have been reported in association with LQTS (Stenson P et al., 2014), supporting the functional significance of this residue and this region of the protein. R539Q results in a semi-conservative amino acid substitution of a positively charged Arginine with a neutral Glutamine at a position that is highly conserved in other species. In addition, in silico analysis predicts R539Q is probably damaging to protein structure/function.However, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000556413 SCV000627381 uncertain significance Long QT syndrome 2017-01-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 539 of the KCNQ1 protein (p.Arg539Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (rs199472794, ExAC no frequency). This variant has been reported in an individual referred for long QT syndrome genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67042). This variant identified in the KCNQ1 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNQ1-topology. 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"). A different missense substitution at this codon (p.Arg539Trp) has been determined to be pathogenic (PMID: 23098067, 23251633, 23631430, 24681627, 25559286). This suggests that the arginine residue is critical for KCNQ1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584804 SCV000692511 likely pathogenic Long QT syndrome 1 2017-03-14 criteria provided, single submitter research The KCNQ1 Arg539Gln has been reported previously in a case control study of 2500 patients referred for long QT genetic testing (Kapplinger JD, et al., 2009), as well as a long QT patient (Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust ClinVar: SCV000089124). Interestingly, another rare variant at this position (KCNQ1 Arg539Trp) has been classified as pathogenic; suggesting that an amino acid substitution at this site may not be tolerated. We have identified this KCNQ1 Arg539Gln variant in one long QT case, and the variant was found to segregate to another affected family member. The variant is absent in the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect. This variant was discussed at our multidisciplinary pathogenicity meeting and based on rarity in the general population, pathogenic classification of another amino acid substitution at the same position, our familial data, in silico tools supportive of a deleterious effect and because the proband has a typical LQT1 phenotype which is known to be caused by genetic variation in only the KCNQ1 gene, we classify KCNQ1 Arg539Gln as "likely pathogenic".
Ambry Genetics RCV000619224 SCV000737705 uncertain significance Cardiovascular phenotype 2016-08-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057605 SCV000089124 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: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.