Submissions for variant NM_000218.3(KCNQ1):c.1781G>A (p.Arg594Gln)

gnomAD frequency: 0.00001  dbSNP: rs199472815

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000046031	SCV000074044	pathogenic	Long QT syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 594 of the KCNQ1 protein (p.Arg594Gln). This variant is present in population databases (rs199472815, gnomAD 0.005%). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 10973849, 11530100, 12402336, 15840476, 16818214, 17905336, 19716085, 24218437). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53018). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 15051636, 15935335, 20662986, 25453094). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000182228	SCV000234531	pathogenic	not provided	2022-07-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19862833, 27470144, 22956155, 11530100, 12402336, 15935335, 19716085, 22949429, 20662986, 19825999, 23098067, 17329209, 15051636, 25453094, 24912595, 22885918, 17329207, 15140888, 11140949, 26481773, 22629021, 19815527, 17470695, 26669661, 21451124, 16540748, 10973849, 14678125, 15840476, 16818214, 17905336, 24218437, 29740400, 29677589, 31963859, 30609406, 30974404, 31447099, 31737537, 33777698, 33087929, 34135346, 32686758, 34505893)
Ambry Genetics	RCV000247524	SCV000319597	pathogenic	Cardiovascular phenotype	2021-11-18	criteria provided, single submitter	clinical testing	The p.R594Q pathogenic mutation (also known as c.1781G>A), located in coding exon 15 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1781. The arginine at codon 594 is replaced by glutamine, an amino acid with highly similar properties, and is located in the C-terminal cytoplasmic assembly domain. This alteration has been reported in multiple patients with long QT syndrome (Splawski I et al. Circulation. 2000;102(10):1178-85; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Cava F et al. Mol Genet Metab Rep. 2021 Jun;27:100743). Functional studies have shown this alteration reduces cell surface channel expression and results in a trafficking defect (Westenskow P et al. Circulation. 2004;109(15):1834-41; Kanki H et al. J Biol Chem. 2004;279(32):33976-83; Zhang M et al. Proc Natl Acad Sci U.S.A. 2014;111(50):E5383-92). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000057637	SCV000712007	likely pathogenic	Congenital long QT syndrome	2019-08-21	criteria provided, single submitter	clinical testing	The p.Arg594Gln variant in KCNQ1 has been reported in the heterozygous state in at least 8 individuals with long QT syndrome (LQTS) and segregated with disease in at least 3 affected relatives from at least 2 families (Splawski 2000, Jongbloed 2002, Zareba 2003, Tester 2006, Chung 2007, Moss 2007, Giudicessi 2012, Cueno 2013). It was also identified in the compound heterozygous state in 2 individuals with Jervell and Lange-Nielsen syndrome (JLNS), in 1 individual with severe LQTS who did not appear to have hearing loss (Huang 2001, Westenskow 2004, Mura 2108). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 53018) and has been identified in 7/282350 pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with late-onset, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that this variant impacts protein function (Huang 2001, Westenskow 2004, Wilson 2005, Horr 2011, Harmer 2014, Zhang 2014) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg594Gln variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PS3_supporting, PS4_Moderate, PM2_Supporting, PP3, PP1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046031	SCV000919558	pathogenic	Long QT syndrome	2021-06-21	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 (IPR013821) 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 2e-05 in 251368 control chromosomes. c.1781G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (e.g. Splawski_2000, Amin_2012). These data indicate that the variant is very likely to be associated with disease. Multiple publications report in-vitro experimental evidence demonstrating impaired trafficking and activity of the protein channels in cells expressing the variant (e.g. Wilson_2005, Zhang_2014). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258107	SCV001434953	pathogenic	Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1	2019-02-21	criteria provided, single submitter	clinical testing	The c.1781G>A (p.Arg594Gln) variant in the KCNQ1 gene has been reported in multiple unrelated individuals affected with long QT Syndrome (PMID 10973849, 15051636, 19716085, 23124029, 25453094, 27041096) and is extremely rare in general population. This variant has also been reported in compound heterozygous state in one individual affected with Jervell and Lange-Nielsen syndrome (PMID 11530100). Experimental studies have shown that this missense change results in reduction or loss of channel function (PMID 15051636,15140888, 25453094). Arg594 is highly conserved and multiple lines of algorithms predict deleterious effect of the p.Arg594Gln change. Therefore, we classify this c.1781G>A (p.594Gln) variant in the KCNQ1 gene as pathogenic.
Clinical Genetics Laboratory, Region Ostergotland	RCV001731336	SCV001984991	pathogenic	Long QT syndrome 1	2020-11-24	criteria provided, single submitter	clinical testing	PS4, PM1, PP3, PM5, PM2
AiLife Diagnostics, AiLife Diagnostics	RCV000182228	SCV002502826	likely pathogenic	not provided	2021-12-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496702	SCV002811046	pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-07-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000182228	SCV003820909	pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224128	SCV003920106	pathogenic	Atrial fibrillation, familial, 3; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-03-30	criteria provided, single submitter	clinical testing	KCNQ1 NM_000218.2 exon 15 p.Arg594Gln (c.1781G>A): This variant has been reported in the literature in several individuals with LQTS, segregating with disease in at least two affected family members (Splawski 2000 PMID:10973849, Huang 2001 PMID:11530100, Jongbloed 2002 PMID:12402336, Westenskow 2004 PMID:15051636, Tester 2005 PMID:15840476, Tester 2006 PMID:16818214, Chung 2007 PMID:17905336, Kapplinger 2009 PMID:19716085, Giudicessi 2012 PMID:22949429). This variant is present in 0.005% (6/128990) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/11-2799254-G-A). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is also present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:53018). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant through abnormal protein trafficking and loss of channel function (Huang 2001 PMID:11530100, Wentenskow 2004 PMID:15051636, Wilson 2005 PMID:15935335, Zhang 2014 PMID:25453094). In summary, this variant is classified as pathogenic based on the data above.
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV001731336	SCV004024215	pathogenic	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003591639	SCV004358441	pathogenic	Cardiac arrhythmia	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 594 in the C-terminal cytoplasmic region of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased cell surface protein expression and loss of potassium channel function (PMID: 15051636, 15140888, 20662986) by causing retention of the mutant protein in the endoplasmic reticulum and disturbing channel trafficking (PMID: 15935335, 24912595). This variant has been reported in up to 30 individuals affected with long QT syndrome, including over ten pediatric probands (PMID: 10973849, 12402336, 14678125, 15051636, 16818214, 17470695, 17905336, 19841300, 20662986, 22949429, 24218437, 24912595, 25453094, 27041096, 32421437), and 17 individuals suspected of having long QT syndrome (PMID: 15840476, 19716085). This variant has been observed in two biallelic individuals affected with Jervell and Lange-Nielsen Syndrome (PMID: 11140949, 11530100, 29677589). This variant has been identified in 7/282350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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.
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).
Clinical Genetics, Academic Medical Center	RCV000182228	SCV001917665	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000182228	SCV001952266	pathogenic	not provided		no assertion criteria provided	clinical testing