ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.1781G>A (p.Arg594Gln) (rs199472815)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000247524 SCV000319597 pathogenic Cardiovascular phenotype 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other strong data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s)
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057637 SCV000089156 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:11530100;PMID:12402336;PMID:14678125;PMID:15051636;PMID:15840476;PMID:16818214;PMID:17329209;PMID:17905336;PMID:19716085;PMID:19841300;PMID:11140949;PMID:17470695;PMID:17329207;PMID:15935335). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000182228 SCV000234531 pathogenic not provided 2018-11-21 criteria provided, single submitter clinical testing The R594Q pathogenic variant in the KCNQ1 gene has been reported multiple times in association with LQTS (Splawski et al., 2000; Tester et al., 2005; Tester et al., 2006; Chung et al., 2007; Stattin et al., 2012; Cuneo et al., 2013). This variant has also been reported in individuals with JLNS, or a severe LQTS phenotype without hearing loss, who also harbor a second KCNQ1 variant on the opposite allele (in trans) (Tyson et al., 2000; Huang et al., 2001; Westenskow et al., 2004; Mura et al., 2018). R594Q has been observed in the heterozygous state in multiple other unrelated individuals with LQTS referred for genetic testing at GeneDx. This variant has been shown to segregate with LQTS in multiple affected relatives from unrelated families, as reported by Cuneo et al. (2013), Westenskow et al. (2004), and observed at GeneDx. The R594Q variant is observed in 6/126,580 alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016).R594Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Multiple functional studies demonstrate that R594Q results in a complete loss of KCNQ1 channel function due to a trafficking defect of the mutated channel to the plasma membrane (Huang et al., 2001; Westenskow et al., 2004; Zhang et al., 2014). Other pathogenic or likely pathogenic missense variants in nearby residues (G589D, G589R, A590T, R591H, R591L, R591C) and at the same residue (R594P) have been reported in association with LQTS in HGMD (Stenson et al., 2014) and at GeneDx, further supporting the functional importance of this residue and region of the protein.In summary, R594Q in the KCNQ1 gene is interpreted as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000046031 SCV000919558 pathogenic Long QT syndrome 2018-09-04 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.1781G>A (p.Arg594Gln) results in a conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 277214 control chromosomes. c.1781G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (Splawski_2000, Amin_2012). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000046031 SCV000074044 pathogenic Long QT syndrome 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 594 of the KCNQ1 protein (p.Arg594Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs199472815, ExAC 0.01%). This variant has been reported in multiple families and individuals with long QT syndrome (PMID: 10973849, 12402336, 15840476, 16818214, 17905336, 19716085, 24218437) and has been observed in the compound heterozygous state in an individual with Jervell and Lange-Nielsen syndrome (PMID: 11530100). ClinVar contains an entry for this variant (Variation ID: 53018). This variant identified in the KCNQ1 gene is located in the cytoplasmic subunits assembly region of the resulting protein (PMID: 19841300). For more information about the location of this variant, please visit Experimental studies have shown that this missense change is deficient in protein trafficking (PMID: 15935335, 25453094) and is also unable to transmit current normally (PMID: 15051636, 20662986). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000057637 SCV000712007 likely pathogenic Congenital long QT syndrome 2016-09-13 criteria provided, single submitter clinical testing The p.Arg594Gln variant in KCNQ1 has been reported in the heterozygous state in >25 individuals with long QT syndrome, as well as in the compound heterozygous s tate in one individual who presented with a more severe clinical phenotype that did not result in Jervell and Lange Nielsen syndrome (JLNS). This variant segreg ated with disease in 3 affected relatives from 2 families (Tyson 2000, Huang 200 1, Splawski 2000, Zareba 2003, Westenskow 2004, Tester 2005, Tester 2006, Chung 2007, Moss 2007, Kapplinger 2007). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 53018) and has been identified i n 6/126580 European chromosomes by the Genome Aggregation Database (gnomAD, http ://; dbSNP rs199472815). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathoge nic variants may be present at a low frequency in the general population. In vit ro functional studies provide some evidence that the p.Arg594Gln variant impairs but does not completely abolish channel activity (Huang 2001, Westenskow 2004, Zhang 2014). In summary, although additional studies are required to fully esta blish its clinical significance, the p.Arg594Gln variant is likely pathogenic. A CMG/AMP Criteria applied: PS4, PP1, PP3
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000182228 SCV000280151 likely pathogenic not provided 2015-07-23 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.Arg594Gln Given the strong case data and absence in controls, we consider it likely disease causing. This variant has been reported in at least 2 cases with Jervell and Lang Nielsen Syndrome. There is weak segregation data on the variant. Splawski et al (2000) first reported the variant in 3 families out of 262 unrelated individuals with documented QTc of > or = to 460ms and/or torsade de pointes, VF, arrest or aborted arrest. The subject population was from North America and Europe. Tyson et al (2000) described a proband with the variant and Jervell and Lang Nielsen Syndrome. The individual was of British descent and had severe congenital deafness, h/o syncope and QTc of 650 ms. Huang et al (2001) reported of 1 case with the p.Arg594Gln variant and JLNS. The case was male, from Northern Europe with an average QTc of 445ms and no family or personal history of SCD. Jongbloed et al (2002) noted 1 out of 32 probands with LQTS from the Dutch and Belgian population. No additional phenotype data was provided. In 2003, Zareba et al reported 3 cases out of 294 LQTS genotype positive subjects. The subjects were derived from the International LQTS Registry (which includes samples from Rochester, Charlottesville, Houston, Milan and Jerusalem). It is unclear if these cases are unrelated and no phenotype data was provided on the case. In 2004 Westenskow et al did show segregation of p.Arg594Gln with 3 affected individuals in a family. One of the individuals was a compound heterozygote for p.Val310Ile in the KCNQ1 gene; the remaining 2 affecteds did not carry p.Val310Ile in KCNQ1. One affected individual with p.Arg594Gln only had no symptoms and had a QTc of 440 ms. A family member considered unaffected was genotype negative for both variants. Tester et al (2005) reported 2 cases with the variant out of 541 unrelated patients referred to Mayo Clinic’s SCD Genomics Lab between August 1997 and July 2004. A year later Tester et al reported a 15 year old Caucasian female with history of syncope, QTc of 500ms and negative family history of SCD. This publication was testing the efficacy of a genotyping method and the proband was tested in a prior study but no variants were identified thus Tester et al identified the variant upon rerunning genetic testing- this case is additive. Cheung et al (2007) genotyped 84 individuals with either Brugada or LQTS and an average QTc of 500 ms and identified one proband with p.Arg594Gln in the KCNQ1 gene. The patient was a 9 year old male of European descent who had a water related syncopal episode and a QTc of 470 ms. Moss et al (2007) reported 11 subjects with the variant out of 600 individuals with genetically confirmed KCNQ1 variants. The study population originated from the LQTS Registry (which contained samples from US, Netherlands and Japan) and it is unclear if these cases are related. In 2009, Kapplinger et al reported 15 unrelated individuals with p.Arg594Gln out of 2500 patients referred to PGX Health for genetic testing between May 2004 and October 2008. Of note in considering the 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). Kappa et al (2009) also reported 3 cases of Caucasian descent out of 388 unrelated individuals with a Schwartz score of >or = 4 or QTc >or= to 480 ms. It is likely that these cases overlap with the Kapplinger cases above. In 2012, Giudicessi et al also reported of cases with the variant and Schwartz score > or= to 3.5 or QTc 480 ms but it is highly likely that these are the same cases as Kapplinger et al. This is a semi conservative amino acid change with a polar positive Arginine replaced with a polar neutral Glutamine. The amino acid change occurs at the subunit assembly region KCNQ1 channel. SIFT predicts the amino acid change to be tolerated in the resulting protein while PolyPhen predicts the change to be probably damaging to the resulting protein. Missense variants at and in nearby codons (p.Arg 594Pro, p.Arg 591His, p.Arg591Cys p.Gly589Asp) have been reported in association with LQTS. This variant is listed in the hearing.harvard database. There are no functional studies involving mouse models. However studies involving human K+ channels with the variant have a 3 times higher proportion of ER co localization compared to wild type channels (Wilson et al 2005). In 2007, Howard et al analyzed the structure of the K+ channel with the variant in question and noted that mutant channels have a much lower elution volume than wild type channels. In total the variant has not been seen in ~8512 individuals from published control samples and publicly available general population datasets. Splawski et al (2000) report that p.Arg594Gln was absent in 200 presumably healthy controls whose ancestry was not specified. Westenskow et al (2004) reported that the variant was absent in 462 presumably healthy individuals of unspecified ethnicity. Chung et al did not identify p.Arg594Gln in 50 presumable healthy controls of unspecified race. Kapplinger et al (2009) reported that p.Arg594Glnwas not observed in 1300 presumably healthy controls (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). The variant is listed in dbSNP with the rs199472815 with submission from Royal Brompton & Harefield NHS Foundation Trust Cardiovascular Biomedical Research Unit; there is no allele frequency data available. The variant is listed in NHLBIs ClinVar database with 3 submissions (2 from Invitae and 1 Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust). It is classified as “pathogenic, likely pathogenic” by Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust (Last updated Feb 24th 2014). The variant was not observed in the 1000 genomes dataset. In addition there is no variation at codon 594 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of October 13, 2014).

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