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rs199472815

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000218.3(KCNQ1):c.1781G>A(p.Arg594Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R594P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

9
9
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 7.54
Variant links:
Genes affected
KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000218.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-2778024-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.89
PP5
Variant 11-2778024-G-A is Pathogenic according to our data. Variant chr11-2778024-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2778024-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.1781G>A p.Arg594Gln missense_variant 15/16 ENST00000155840.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.1781G>A p.Arg594Gln missense_variant 15/161 NM_000218.3 P1P51787-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
250968
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135742
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461426
Hom.:
0
Cov.:
32
AF XY:
0.0000248
AC XY:
18
AN XY:
727042
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000956
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 11, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsDec 23, 2021- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 18, 2022This 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) -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely pathogenic, no assertion criteria providedclinical testingStanford Center for Inherited Cardiovascular Disease, Stanford UniversityJul 23, 2015Note 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 o -
Long QT syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 18, 2023This 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. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This 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. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 21, 2021Variant 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. -
Long QT syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory - Cardiogenetics, CHU de NantesAug 01, 2023- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Region OstergotlandNov 24, 2020PS4, PM1, PP3, PM5, PM2 -
Congenital long QT syndrome Pathogenic:1Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-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. -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 21, 2019The 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. -
Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 09, 2021- -
Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineFeb 21, 2019The 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. -
Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021KCNQ1 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. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 18, 2021The 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. -
Cardiac arrhythmia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 15, 2023This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
CardioboostArm
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.49
Cadd
Pathogenic
33
Dann
Pathogenic
1.0
DEOGEN2
Pathogenic
0.90
D;.;.;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.93
D;D;D;T
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.5
M;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-2.4
N;.;N;.
REVEL
Pathogenic
0.85
Sift
Benign
0.047
D;.;T;.
Sift4G
Uncertain
0.031
D;.;T;.
Polyphen
1.0
D;.;D;.
Vest4
0.79
MutPred
0.65
Loss of MoRF binding (P = 0.0174);.;.;.;
MVP
0.97
MPC
1.3
ClinPred
0.85
D
GERP RS
3.1
Varity_R
0.47
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199472815; hg19: chr11-2799254; API