ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.704A>G (p.Lys235Arg) (rs12720458)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045957 SCV000073970 pathogenic Long QT syndrome 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 362 of the KCNQ1 protein (p.Lys362Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs12720458, ExAC 0.01%). This variant has been reported in several unrelated individuals affected with long QT syndrome (PMID: 15840476, 22949429, Invitae). In addition, it has also been observed in an individual with Jervell and Lange-Nielsen syndrome (PMID: 15781747). ClinVar contains an entry for this variant (Variation ID: 52953). Experimental studies have shown that this missense change leads to a dysfunctional KCNQ1 channel (PMID: 24947509, 26546361). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000223836 SCV000234474 likely pathogenic not provided 2021-06-03 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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) This variant is associated with the following publications: (PMID: 22581653, 31447099, 24077912, 27535533, 24947509, 26546361, 30609406, 30755392, 29197658, 27831900, 15840476, 27041150, 15781747, 22949429, 19841300, 19716085, 23392653, 25525159)
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
CHLA 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; Abnormality of the cerebral white matter; Abnormality of the nares; Postnatal microcephaly; Diffuse white matter abnormalities; Generalized neonatal hypotonia; Enlarged naris; Congenital 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 2 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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 ( 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 Health, Inc RCV001179841 SCV001344629 uncertain significance Arrhythmia 2020-10-09 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 362 of the KCNQ1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Functional studies have shown that this missense affects current amplitude in vitro and disrupts the potassium channel regulation in ciliogenesis (PMID: 24947509, 26546361). However, clinical relevance of this observation is not known. This variant has been reported in two individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 23392653). This variant has been reported in multiple individuals affected with long QT syndrome (PMID: 19841300, 22949429) or referred for long QT syndrome genetic testing (PMID: 15781747, 19716085). Due to author overlap in these articles, it is not clear how many unique heterozygous long QT syndrome patients have been identified in the literature. This variant has been identified in 10/251350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, there is a suspicion that this variant may play a role in autosomal recessive Jervell and Lange-Nielsen syndrome, and this variant has been observed in multiple individuals affected with long QT syndrome. However, as noted by Whiffin et al., (PMID: 30609406), this variant has also been observed in the general population and it remains to be determined whether this variant segregates with disease in family studies. Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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 PS4_Moderate, PM3, PS3_Supporting PP3, PP5
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

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