ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.188G>A (p.Arg63Gln) (rs120074178)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046088 SCV000074101 pathogenic Long QT syndrome 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 190 of the KCNQ1 protein (p.Arg190Gln). 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 (ExAC no frequency). This variant has been reported to segregate with long QT syndrome in several families (PMID: 8528244, 10728423, 20660394). In addition, the variant has been observed in individuals with Jervell and Lange-Nielsen syndrome (PMID: 22629021) and unrelated individuals with long QT syndrome (PMID: 17470695). This variant is also known as p.Arg61Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 3117). Experimental studies have shown that this missense change leads to a loss of KCNQ1 channel activity (PMID: 10376919, 10728423). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182086 SCV000234389 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing The R190Q pathogenic variant in the KCNQ1 gene has been reported multiple heterozygous individuals in association with LQTS, and at least two individuals with Jervell and Lange-Nielsen syndrome who were either homozygous for this variant or compound heterozygous for R190Q and a second variant in the KCNQ1 gene (Wang et al., 1996; Donger et al., 1997; Splawski et al., 2000; Tester et al., 2005; Moss et al., 2007; Kapa et al., 2009; Kapplinger et al., 2009; Moretti et al., 2010; Hofman et al., 2011; Crotti et al., 2012; Gao et al., 2012; Vyas et al., 2016; Ebrahim et al., 2017). It is also classified as a pathogenic variant by another clinical laboratory (ClinVar SCV000074101.4; Landrum et al., 2016). Additionally, this variant has been reported to segregate with LQTS in several affected heterozygous relatives from multiple families (Wang et al., 1996; Donger et al., 1997; Chouabe et al., 2000; Moretti et al., 2010; Crotti et al., 2012). Moreover, the R190Q variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R190Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this substitution occurs at a position that is conserved across species. Furthermore, functional studies in both mammalian cultured cells and induced pluripotent stem cell-derived cardiomyocytes showed that the co-expression wild-type and R190Q mutant channels alters the delayed rectifier potassium current through a dominant negative effect (Chouabe et al., 2000; Moretti et al., 2010). Finally, other pathogenic missense variants at the same residue (R190W, R190L) have also been reported in association with LQTS (Napolitano et al., 2005; Kapplinger et al., 2009), supporting the functional importance of this residue.
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000003264 SCV000240225 pathogenic Long QT syndrome 1 2013-01-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000588393 SCV000695991 pathogenic Cardiovascular phenotype 2017-05-05 criteria provided, single submitter clinical testing Variant summary: The KCNQ1 c.569G>A (p.Arg190Gln) variant causes a missense change involving the alteration of a highly conserved nucleotide. The variant is located within S2S3 cytoplasmic loop of transmembrane domain and 4/5 in silico tools predict a damaging outcome for this variant. The Arg190Gln was to proven to be a functionally abrogated by experimental studies where mutation led to a non-functional channel, independently of the presence of stimulation subunit IsK (Chouabe, 2000; Wang, 1999). The c.1550G>A was not identified in large, broad control datasets of ExAC and gnomAD (~120332 and ~246272 chrs tested, respectively), but is found in multiple LQTS individuals and segregated with the disease in several families (Wang, 1996; Chouabe, 2000; Gao, 2012). In addition, Arg190 appears to be a mutational hot-spot, as other alterations of this codon have been reported in association with LQTS (p.Arg190Leu, p.Arg190Trp). Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
Ambry Genetics RCV000588393 SCV000737871 pathogenic Cardiovascular phenotype 2016-12-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Deficient protein function in appropriate functional assay(s)
OMIM RCV000003264 SCV000023422 pathogenic Long QT syndrome 1 2010-10-07 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057706 SCV000089225 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:8528244;PMID:9386136;PMID:10728423;PMID:11668638;PMID:14678125;PMID:15051636;PMID:15840476;PMID:19716085;PMID:19841300;PMID:10376919;PMID:17470695;PMID:9693036;PMID:22456477;PMID:22629021). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000182086 SCV000280158 pathogenic not provided 2014-12-02 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Arg190Gln Given the strong case data and absence in controls, we consider this variant to be very likely disease causing. This variant has been seen in at least 10 unrelated cases of Long QT syndrome with moderate segregation data. This variant was previously reported as p.Arg61Gln and p.Arg95Gln. Wang et al (1996) identified KCNQ1 as the LQT1 locus and reported the first KCNQ1 variants, including p.Arg190Gln in a family with two affected individuals (reported as p.Arg61Gln). Donger et al (1997) observed the the variant in a family with long QT from their French cohort. It appears that multiple affected family members had the variant, though it is unclear from the data presented how many. Chouabe et al (2000) reported a family with long QT syndrome and the p.Arg190Gln variant. Of the four individuals in the family who carried the variant, three had a prolonged QT interval (472-530ms). Larsen et al (2001) observed the variant in a long QT patient from their Dutch cohort. Westenskow et al (2004) (Keating's group) observed the variant in a family with long QT syndrome who also carried a variant in KCNE1. The variant is reported in the Familion compendium in 3 of 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009, likely same cases as Kapa et al 2009). Of note in considering the other cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Gao et al reported the variant in a patient from their Chinese cohort with JLNS who was a compound heterozygote. Hofman et al (2010) reported on 14 long QT syndrome variants, including this one, that were found recurrently in the Netherlands. The p.Arg190Gln variant was seen in three different probands. The variant was included in several papers on genotype-phenotype correlations, however the cases likely overlap with prior reports (Moss et al 2007, Barsheshet et al 2012). We have seen this variant in one other family in our center, present in both mother and son with long QT syndrome. (note that the cases reported by Wang et al, Zareba et al, Moss et al, and Horr et al may not be unique) Chouabe et al (2000) reported that the variant led to a non-functional channel in their studies. Moretti et al (2010) studied patient-specific IPS cells with the p.Arg190Gln variant and observed a dominant-negative trafficking defect associated with a reduction in the I(Ks) current and altered channel activation and deactivation properties. The variant occurs in the S2-S3 domain, one of the cytoplasmic loops. Variants in this region are likely to pathogenic (Kapa et al 2009). Moss et al (2007) classified the variant's effect as haploinsufficient and found that such variants confer a lower risk of arrhythmias than variants with a dominant negative effect. However, a later report from the same group re-classified the effect as dominant negative (Barsheshet et al 2012). This same study also found a higher risk of events, as well as a greater response to beta-blockers, associated with variants in the cytoplasmic loop. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging; SIFT predicts it to be deleterious. Other variants have been reported in association with disease at this codon (p.Arg190Leu, p.Arg190Trp) and nearby codons (p.Lys183Arg, p.Lys183Met, p.Tyr184His, p.Tyr184Ser, p.Gly186Arg, p.Gly186Ser, p.Leu187Pro, p.Gly189Glu, p.Gly189Arg, p.Leu191Pro, p.Arg192His, p.Arg192Pro, p.Arg192Cys, p.Phe193Leu, p.Ala94Pro, p.Arg195Gln, p.Arg195Trp, p.Ile98Val, p.Ser199Ala). In total the variant has not been seen in ~8000 published controls and individuals from publicly available population datasets. There is no variation at codon 190 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6500 Caucasian and African American individuals (as of December 27th, 2013). The variant was not observed in the following lpublished control samples: Wang et al (1996) did not observe the variant in over 200 control individuals, Kapplinger et al (2009) did not observe the variant in 1300 presumed healthy individuals. The variant is listed in dbSNP (rs120074178) as a pathogenic variant.

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