Submissions for variant NM_000218.3(KCNQ1):c.1085A>G (p.Lys362Arg)

gnomAD frequency: 0.00001  dbSNP: rs12720458

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045957	SCV000073970	pathogenic	Long QT syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 362 of the KCNQ1 protein (p.Lys362Arg). This variant is present in population databases (rs12720458, gnomAD 0.008%). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 15781747, 15840476, 22949429; Invitae). 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: 52953). 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: 24947509, 26546361). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000223836	SCV000234474	likely pathogenic	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Observed in two unrelated families with LQTS that also harbored another pathogenic KCNQ1 variant on the opposite allele (in trans), yet two compound heterozygous individuals did not have a history of hearing loss (Giudicessi et al., 2013); Also reported in individuals with Jervell-Lange Nielsen syndrome referred for genetic testing at GeneDx and in published literature (Darbar et al., 2005); Identified in a patient with cardiomyopathy and history of unexplained cardiac arrest but normal QTc interval (Grondin et al., 2022); the authors suggest this is an incidental finding and the cardiac arrest is due to cardiomyopathy; Functional studies are not conclusive regarding the potential effect of this variant on cardiac ion channel function (Eckey et al., 2014; Slaats et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19716085, 19841300, 22949429, 25525159, 27041150, 15840476, 27831900, 29197658, 30755392, 30609406, 26546361, 31447099, 22581653, 31589614, 34135346, 33087929, 34319147, 35352813, 15781747, 23392653, 24077912, 24947509, 23631430, Sanatani2022[Article])
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000045957	SCV000747933	likely pathogenic	Long QT syndrome	2016-11-29	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735400	SCV000854555	likely pathogenic	Polyhydramnios; High palate; Generalized hypotonia; Neonatal hypotonia; Decreased fetal movement; Toe clinodactyly; Abnormal cerebral white matter morphology; Abnormal nostril morphology; Secondary microcephaly; Diffuse white matter abnormalities; Generalized neonatal hypotonia; Enlarged naris; Primary microcephaly		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762835	SCV000893194	pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000057548	SCV000966929	likely pathogenic	Congenital long QT syndrome	2020-07-03	criteria provided, single submitter	clinical testing	The p.Lys362Arg variant in KCNQ1 has been reported in the heterozygous state in at least 4 individuals with long QT syndrome (LQTS), in the compound heterozygous state with another well-established pathogenic variant in 2 individuals with an early-onset, more severe LQTS phenotype without hearing loss and segregated with prolonged QT in 2 affected relatives from 2 families (Kapa 2009 PMID: 19841300, Guidicessi 2012 PMID: 22949429, Giudicessi 2013 PMID: 23392653, GeneDx pers. comm., Invitae pers. comm., LMM data). It has also been reported in the compound heterozygous state in 1 individual with Jervell-Lange-Nielsen syndrome (JLNS; Darbar 2005 PMID: 15781747). Additionally, it has been identified in at least 5 individuals that have been referred for long QT syndrome (LQTS) testing; however, their detailed clinical information was not available (Tester 2005 PMID: 15840476, Kapplinger 2009 PMID: 19716085). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 52953) and has been identified in 0.008% (9/113664) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Lys362Arg variant may impact the protein (Slaats 2015 PMID: 26546361, Eckey 2014 PMID: 24947509) and computational prediction tools and conservation analysis suggest that the p.Lys362Arg variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Lys362Arg variant is likely pathogenic for autosomal dominant LQTS. In the presence of another pathogenic variant in trans (on the other copy of the KCNQ1 gene), this variant may also cause a more severe form of LQTS with an earlier age of onset. ACMG/AMP Criteria applied: PM3_Strong; PP3; PS3_Supporting.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000851291	SCV000993563	likely pathogenic	Long QT syndrome 1	2019-06-27	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001841623	SCV001344629	likely pathogenic	Cardiac arrhythmia	2023-07-28	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 362 of the KCNQ1 protein. This variant is found within a highly conserved region (a.a.349-391) of the C-terminal cytoplasmic domain. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant affects the potassium channel function (PMID: 24947509, 26546361). This variant has been reported in at least seven unrelated heterozygous individuals affected with or suspected of having long QT syndrome (PMID: 15840476, 19716085, 19841300, 22949429, 32893267, 34404389, 36102233, ClinVar SCV000073970.6). This variant has also been observed in an individual affected with cardiac arrest and cardiomyopathy (PMID: 35352813) and in several asymptomatic individuals as well (PMID: 23392653, 34135346, 35352813). This variant has been reported in compound heterozygous state with a pathogenic variant in the same gene in an individual affected with Jervell and Lange-Nielsen syndrome (PMID: 15781747), as well as in two unrelated individuals affected with severe, early-onset long QT syndrome (PMID: 23392653). This variant has been identified in 10/251350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045957	SCV001372408	likely pathogenic	Long QT syndrome	2020-06-02	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.1085A>G (p.Lys362Arg) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251350 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in KCNQ1 causing Long QT Syndrome (4e-05 vs 8.3e-05), allowing no conclusion about variant significance. c.1085A>G has been reported in the literature in heterozygous individuals with Long QT syndrome and in patients undergoing genetic testing for the same phenotype (Kapa_2009, Kapplinger_2009, Natarajan_2016). The variant was also identified in individuals affected with Long QT syndrome with intact auditory phenotype (Giudicessi_2013) and Jervell-Lange-Nielsen syndrome in compound heterozygous state along with other pathogenic KCNQ1 variants. These data indicate that the variant is likely to be associated with disease. Experimental evidence suggests the variant may impact channel function (Slaats_2015). Six ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic (n=4) or pathogenic (n=2). In addition, several other variants affecting the nearby codons (p.R360G, p.R360M, p.R360T,p.H363N, p.N365H) have been reported (HGMD database), suggesting this area might be a mutational hotspot. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000223836	SCV001713554	likely pathogenic	not provided	2021-03-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000223836	SCV002023225	pathogenic	not provided	2021-09-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162397	SCV003900199	uncertain significance	Cardiovascular phenotype	2022-10-31	criteria provided, single submitter	clinical testing	The p.K362R variant (also known as c.1085A>G), located in coding exon 8 of the KCNQ1 gene, results from an A to G substitution at nucleotide position 1085. The lysine at codon 362 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a number of studies of long QT syndrome (LQTS) clinical genetic testing; however, clinical details were limited and there was significant cohort overlap (Tester DJ et al. Heart Rhythm. 2005;2:507-17; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Kapa S et al. Circulation. 2009;120:1752-60; Giudicessi JR et al. Circ Cardiovasc Genet. 2012;5:519-28; Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61). This alteration was detected in trans with the KCNQ1 p.A341V mutation in a patient with Jervell and Lange-Nielsen Syndrome (JLNS; prolonged QT with congenital deafness); however, it has also been reported in trans with the KCNQ1 p.R518* mutation in two patients with LQTS and normal hearing (Darbar D et al. Circulation. 2005;111:e161; Giudicessi JR et al. Circ Cardiovasc Genet. 2013;6:193-200). This variant has also been detected in cohorts not selected for presence of cardiovascular disease (Zouk et al. Genet Med. 2020 09;22(9):1470-1477; Lacaze P et al. NPJ Genom Med. 2021 Jun;6(1):51). One functional study indicated that this variant does not have a deleterious impact on the interaction of KCNQ1 with PIP2; however, details regarding its overall effect on KCNQ1 function were sparse (Eckey K et al. J Biol Chem. 2014;289:22749-58). In another study, KCNQ1 p.K362R was unable to rescue ciliogenesis in mouse kidney cells following KCNQ1 siRNA-mediated depletion; however, the physiological relevance with respect to KCNQ1 function in human heart is unclear (Slaats GG et al. J Cell Sci. 2015;128:4550-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
New York Genome Center	RCV003448253	SCV003925210	likely pathogenic	Atrial fibrillation, familial, 3; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2023-07-18	criteria provided, single submitter	clinical testing	The c.1085A>G p.(Lys362Arg) variant identified in the KCNQ1 gene has previously been reported in the literature in at least 6 individuals with long QT syndrome [PMID: 34798354]. This variant has also been reported at the compound heterozygous state in 3 unrelated individuals with autosomal recessive Jervell-Lange-Nielsen syndrome; one heterozygous carrier was reported with QT prolongation on ECG, whereas another carrier had a normal QT interval [PMID: 15781747; 23392653]. This variant has been reported in ClinVar [ClinVar ID: 52953] as Variant of Uncertain Significance (2 submissions), Likely Pathogenic (8 submissions) or Pathogenic (3 submissions). The c.1085A>G variant is observed in 9 alleles (~0.003 % minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1085A>G p.(Lys362Arg) variant in KCNQ1 is located in exon 8 of this 16-exon gene, and predicted to replace an evolutionarily conserved lysine amino acid with arginine at position 362 in the c-terminal region of the encoded protein. Functional studies have shown that this missense variant affects the potassium channel regulation in renal ciliogenesis and that is involved in anionic phospholipids binding. However, these studies are not conclusive regarding the potential effect of this variant on the cardiac ion channel [PMID: 21084310, 24947509, 26546361]. In silico predictions are in favor of damaging effect for KCNQ1 p.(Lys362Arg) [REVEL = 0.964)]. Variants nearby p.(Lys362Arg) residue within the C-terminus domain have been reported in the literature in association with long QT syndrome [PMID:19716085, 34505893,] and ClinVar [ClinVar ID: 52955]. Based on available evidence this c.1085A>G p.(Lys362Arg) variant identified in the KCNQ1 gene is reported as Likely Pathogenic.
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV000851291	SCV004024173	likely pathogenic	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV003330078	SCV004037372	likely pathogenic	Atrial fibrillation, familial, 3; Long QT syndrome 1; Short QT syndrome type 2	2019-11-27	criteria provided, single submitter	clinical testing	The p.Lys362Arg variant in the KCNQ1 gene is a heterozygous missense variant, which results in the substitution of the highly conserved lysine residue at the 362 position to arginine. This variant localizes to coding exon 8 of the KCNQ1 gene and is within the helical transmembrane region of the protein. This variant is predicted to be deleterious and damaging to protein structure and/or function based on in silico analyses (damaging by SIFT, probably damaging by PolyPhen2).This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (10/251,350), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in the heterozygous state in individuals with LQTS (PMIDs: 15840476, 19841300, 19716085, 22949429, and 27831900). This variant has also been seen in the compound heterozygous state in three individuals with autosomal recessive JLNS with or without hearing loss ((PMIDs: 23392653 and 15781747).
Baylor Genetics	RCV000851291	SCV004040904	likely pathogenic	Long QT syndrome 1	2023-03-28	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335077	SCV004046379	likely pathogenic	KCNQ1-Related Disorders		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in several unrelated individuals affected with long QT syndrome (PMID: 15840476, 22949429). It has also been reported in the compound heterozygous state in 1 individual with Jervell-Lange-Nielsen syndrome (PMID: 15781747). Missense variation is an established mechanism of disease for KCNQ1-related disorders (HGMD). Experimental studies have shown that the presence of this variant leads to an abnormal KCNQ1 channel (PMID: 24947509, 26546361). The c.1085A>G (p.Lys362Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/251350) and thus is presumed to be rare. The c.1085A>G (p.Lys362Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1085A>G (p.Lys362Arg) variant is classified as Likely Pathogenic.
Illumina Laboratory Services, Illumina	RCV000851291	SCV004101338	likely pathogenic	Long QT syndrome 1	2023-08-24	criteria provided, single submitter	clinical testing	The KCNQ1 c.1085A>G (p.Lys362Arg) missense variant results in the substitution of lysine at amino acid position 362 with arginine. This variant has been identified in isolation and as part of a compound heterozygous pair in individuals with long QT syndrome and/or elongated QTc intervals (PMID: 15781747; 22949429; 23392653). A functional study conducted in non-human cells demonstrated that this variant impacts protein function (PMID: 26546361). This variant is located in a hotspot. This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.1085A>G (p.Lys362Arg) variant is classified as likely pathogenic for long QT syndrome.
CeGaT Center for Human Genetics Tuebingen	RCV000223836	SCV004702668	likely pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	KCNQ1: PM1, PS4:Moderate, PM2:Supporting, PP3, PS3:Supporting
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057548	SCV000089067	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:15840476;PMID:19716085;PMID:19841300). 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	RCV000223836	SCV000280139	likely pathogenic	not provided	2014-11-06	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.Lys362Arg Based on the data reviewed below we consider this variant likely disease causing. The variant has been seen in at least 5 and as many as 8 unrelated cases. There is no segregation data available. Tester et al (2005) observed the variant in 2 of 541 unrelated patients referred for long QT genetic testing in a research laboratory at Mayo lead my Dr. Michael Ackerman. Individual phenotype is not reported, however the average QTc for the sample was 482 ms and 29% of subjects had a Schwartz score =4. The variant was reported in 5 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). 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). Kapa et al (2009) reported a Caucasian patient with this variant, however, that case may be redundant with the previously discussed cases since that sample was drawn from the Mayo and Familion cohorts with additional cases from a Dutch cohort. In another paper from Ackerman’s group the variant was reported in two patients with long QT syndrome who were compound heterozygotes but had normal hearing. In both patients the variant was in trans with p.Arg518Ter. Notably they are reported as unrelated families. It is unclear if these cases overlap with prior reports though to be conservative we will assume that they do. In a brief clinical case report on remarkable EKG findings, a team from Vanderbilt reported a woman with JLNS with a QTc over 900 ms in the post-partum period who had p.Ala314Val and p.Lys362Arg in KCNQ1 (Darbar et al 2005). One variant was inherited and the other was de novo (they don’t specify which). No information on the sequencing performed is provided. Given the availability of long QT genetic testing at the time it may have been done either by Dr. Ackerman’s research lab (i.e. Tester et al 2005), another research lab, or by Familion/PGxHealth (Kapplinger et al 2009), so there is again potential for overlap with previous cases. PolyPhen-2 predicts the variant to be probably damaging and mutation taster predicts the variant to be disease causing. The lysine at codon 362 is conserved across species, with the exception of elegans, where there is an arginine. The neighboring residues are highly or completely conserved. The variant is in the c-terminal region of the protein. I could find no other variants at the same codon. Variants in nearby codons have been reported in association with long QT syndrome: p.Arg360Gly (Moss et al 2007), p.Gln357His (Moss et al 2007), p.Gln357Arg (Chen et al 2003, Boulet et al 2006), p.Arg360Tyr (Napolitano et al 2005), p.Arg360Met (Kapplinger et al 2009), p.His363Asn (Struijk et al 2006, Hedley et al 2009), p.Asn365His (Kapplinger et al 2009), p.Arg366Gln (Tanaka et al 1997, Splawski et al 2000), and p.Gln367His (Crotti et al 2007). The variant is listed in dbSNP (rs12720458), with data submitted by PharmGKB. Frequency data on HapMap samples is listed (CEU: 0/29, CHB: 0/44, JPT: 0/43, YRI: 0/29). 1 of 138 individuals in a sample named “PA130021341”. The nature of that sample is unclear and instructions provided to get more information didn’t yield the information. The variant is listed in 1000 genomes as a variant imported from dbSNP (opposed to one observed in the 1000 genomes dataset). There is no variation at codon 362 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of Sept 30 2012). In total the variant has not been seen in 1300 published control samples. Kapplinger et al (2009) reported that the variant was not observed in 1,300 presumed healthy individuals (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). Tester et al (2005) did not observe the variant in 744 presumed healthy individuals. However, it seems likely that the sample reported by Tester et al (2005) is included in the sample reported by Kapplinger et al (2009) since both papers point to Ackerman et al (2003) for details on the reference samples. Ackerman et al (2003) notes that samples came from volunteer blood donors or the Human Genetic Cell Repository sponsored by the National Institute of General Medicine and the Coriell institute