ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.776G>A (p.Arg259His) (rs199472720)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057756 SCV000089275 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:16922724). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Color RCV000777479 SCV000913341 likely pathogenic Arrhythmia 2018-10-04 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant is located in the cytoplasmic linker between S4-S5 transmembrane domains of the KCNQ1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental study has shown that this variant alters the channel electrophysiological properties by significantly increasing current density and slowing deactivation (PMID: 26346102). This variant has been reported in an individual affected with long QT syndrome (PMID: 16922724) and two individuals affected with short QT syndrome (PMID: 24291113, 26346102). A different missense substitution at this codon (p.Arg259Cys) is considered pathogenic (Clinvar). This variant has been identified in 5/271834 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
GeneDx RCV000182113 SCV000234416 pathogenic not provided 2018-07-09 criteria provided, single submitter clinical testing The R259H variant in the KCNQ1 gene was initially reported in a 63 year-old asymptomatic male with a prolonged QT interval and a family history of sudden cardiac death (Millat et al., 2006). Subsequently, R259H was observed in two unrelated individuals affected with short QT syndrome and a history of sudden cardiac arrest (Mazzanti et al., 2014; Wu et al., 2015). In vitro functional studies showed R259H caused slower KCNQ1 channel deactivation, resulting in gain-of-function and consistent with QT interval shortening (Wu et al., 2015). Missense variants in the same residue (R259C, R259L) and in nearby residues (V254M, E261Q, E561L, E261D) have been reported in association with LQTS (Stenson et al., 2014). In addition, R259H was not observed with any significant frequency in large population cohorts (Lek et al., 2016). In summary, R259H in the KCNQ1 gene is interpreted as a pathogenic variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709733 SCV000839971 likely pathogenic Long QT syndrome 1 2018-01-30 criteria provided, single submitter clinical testing This c.776G>A (p.Arg259His) variant in the KCNQ1 gene has been reported in multiple LQTS/SQTS patients with significantly higher prevalence than that observed as extremely low in general population according to gnomad database. Arginine at amino acid position 259 is highly conserved during evolution. Arg259Cys, Arg259Gly and Arg259Leu have been reported in multiple LQTS/SQTS patients as deleterious mutations [PMID: 11021476, 15840476, 19716085, 27868350, 21350584]. Multiple in silico predictions suggest this arginine to histidine change is deleterious. Based upon above evidences, this c.776G>A (p.Arg259His) variant in the KCNQ1 gene is classified as likely pathogenic.
Invitae RCV000046124 SCV000074137 pathogenic Long QT syndrome 2018-06-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 259 of the KCNQ1 protein (p.Arg259His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199472720, ExAC 0.01%). This variant has been reported in an individual affected with long QT syndrome (PMID: 16922724) and two individuals affected with short QT syndrome (PMID: 24291113, 26346102). ClinVar contains an entry for this variant (Variation ID: 53101). Experimental studies have shown that this missense change causes slower KCNQ1 channel deactivation (PMID: 26346102). A different missense substitution at this codon (p.Arg259Cys) has been determined to be pathogenic (PMID: 11021476, 21350584, 23158531). This suggests that the arginine residue is critical for KCNQ1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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