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rs120074178

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.569G>A(p.Arg190Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R190L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

15
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 9.36
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 16 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000218.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-2570719-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 11-2570719-G-A is Pathogenic according to our data. Variant chr11-2570719-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570719-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.569G>A p.Arg190Gln missense_variant 3/16 ENST00000155840.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.569G>A p.Arg190Gln missense_variant 3/161 NM_000218.3 P1P51787-1
KCNQ1ENST00000335475.6 linkuse as main transcriptc.188G>A p.Arg63Gln missense_variant 3/161 P51787-2
KCNQ1ENST00000496887.7 linkuse as main transcriptc.308G>A p.Arg103Gln missense_variant 4/165
KCNQ1ENST00000646564.2 linkuse as main transcriptc.478-12716G>A intron_variant

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249462
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135274
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1459946
Hom.:
0
Cov.:
32
AF XY:
0.00000964
AC XY:
7
AN XY:
726396
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Long QT syndrome 1 Pathogenic:4
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 07, 2010- -
Pathogenic, criteria provided, single submitterresearchInstitute of Medical Genetics and Genomics, Sir Ganga Ram HospitalJan 01, 2013- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Region OstergotlandMay 26, 2020PS3, PS4, PM1, PM2, PP1, PP3, PP5, BP2, BP5 -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterNov 24, 2021- -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, no assertion criteria providedclinical testingStanford Center for Inherited Cardiovascular Disease, Stanford UniversityDec 02, 2014Note 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.Arg190Gln Given the strong case data and absence in controls, we consider this variant to be very likely disease causing. This variant has been seen in at least 10 unrelated cases of Long QT syndrome with moderate segregation data. This variant was previously reported as p.Arg61Gln and p.Arg95Gln. Wang et al (1996) identified KCNQ1 as the LQT1 locus and reported the first KCNQ1 variants, including p.Arg190Gln in a family with two affected individuals (reported as p.Arg61Gln). Donger et al (1997) observed the the variant in a family with long QT from their French cohort. It appears that multiple affected family members had the variant, though it is unclear from the data presented how many. Chouabe et al (2000) reported a family with long QT syndrome and the p.Arg190Gln variant. Of the four individuals in the family who carried the variant, three had a prolonged QT interval (472-530ms). Larsen et al (2001) observed the variant in a long QT patient from their Dutch cohort. Westenskow et al (2004) (Keating's group) observed the variant in a family with long QT syndrome who also carried a variant in KCNE1. The variant is reported in the Familion compendium in 3 of 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009, likely same cases as Kapa et al 2009). Of note in considering the other 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). Gao et al reported the variant in a patient from their Chinese cohort with JLNS who was a compound heterozygote. Hofman et al (2010) reported on 14 long QT syndrome variants, including this one, that were found recurrently in the Netherlands. The p.Arg190Gln variant was seen in three different probands. The variant was included in several papers on genotype-phenotype correlations, however the cases likely overlap with prior reports (Moss et al 2007, Barsheshet et al 2012). We have seen this variant in one other family in our center, present in both mother and son with long QT syndrome. (note that the cases reported by Wang et al, Zareba et al, Moss et al, and Horr et al may not be unique) Chouabe et al (2000) reported that the variant led to a non-functional channel in their studies. Moretti et al (2010) studied patient-specific IPS cells with the p.Arg190Gln variant and observed a dominant-negative trafficking defect associated with a reduction in the I(Ks) current and altered channel activation and deactivation properties. The variant occurs in the S2-S3 domain, one of the cytoplasmic loops. Variants in this region are likely to pathogenic (Kapa et al 2009). Moss et al (2007) classified the variant's effect as haploinsufficient and found that such variants confer a lower risk of arrhythmias than variants with a dominant negative effect. However, a later report from the same group re-classified the effect as dominant negative (Barsheshet et al 2012). This same study also found a higher risk of events, as well as a greater response to beta-blockers, associated with variants in the cytoplasmic loop. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging; SIFT predicts it to be deleterious. Other variants have been reported in association with disease at this codon (p.Arg190Leu, p.Arg190Trp) and nearby codons (p.Lys183Arg, p.Lys183Met, p.Tyr184His, p.Tyr184Ser, p.Gly186Arg, p.Gly186Ser, p.Leu187Pro, p.Gly189Glu, p.Gly189Arg, p.Leu191Pro, p.Arg192His, p.Arg192Pro, p.Arg192Cys, p.Phe193Leu, p.Ala94Pr -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 29, 2021Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Functional studies in both mammalian cultured cells and induced pluripotent stem cell-derived cardiomyocytes showed that the co-expression wild-type and R190Q mutant channels alters the delayed rectifier potassium current through a dominant negative effect (Chouabe et al., 2000; Moretti et al., 2010); 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: 23158531, 25825456, 27916777, 27041150, 22456477, 22629021, 10376919, 19862833, 10973849, 19716085, 17470695, 21350584, 15840476, 19841300, 14678125, 20660394, 27470144, 28182229, 22949429, 27485560, 28532774, 9386136, 8528244, 10728423, 28573431, 27917693, 30428582, 31737537, 32383558, 32665702) -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMar 19, 2020PP1_Strong, PS3_Moderate; PS4_Moderate, PM2, PM3, PM5, PM1, PP3 -
Cardiovascular phenotype Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 05, 2017Variant summary: The KCNQ1 c.569G>A (p.Arg190Gln) variant causes a missense change involving the alteration of a highly conserved nucleotide. The variant is located within S2S3 cytoplasmic loop of transmembrane domain and 4/5 in silico tools predict a damaging outcome for this variant. The Arg190Gln was to proven to be a functionally abrogated by experimental studies where mutation led to a non-functional channel, independently of the presence of stimulation subunit IsK (Chouabe, 2000; Wang, 1999). The c.1550G>A was not identified in large, broad control datasets of ExAC and gnomAD (~120332 and ~246272 chrs tested, respectively), but is found in multiple LQTS individuals and segregated with the disease in several families (Wang, 1996; Chouabe, 2000; Gao, 2012). In addition, Arg190 appears to be a mutational hot-spot, as other alterations of this codon have been reported in association with LQTS (p.Arg190Leu, p.Arg190Trp). Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 21, 2018The p.R190Q pathogenic mutation (also known as c.569G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 569. The arginine at codon 190 is replaced by glutamine, an amino acid with highly similar properties, and is located in the S2/S3 transmembrane spanning region of the protein. This mutation has been reported numerous times in individuals with long QT syndrome (LQTS) and in LQTS cohorts, and it has segregated with disease in several families (Wang Q et al. Nat. Genet. 1996;12:17-23; Chouabe C et al. Cardiovasc. Res. 2000;45:971-80; Moss AJ et al. Circulation. 2007;115:2481-9; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Moretti A et al. N. Engl. J. Med. 2010;363:1397-409). The p.R190Q mutation has also been detected in the homozygous and compound heterozygous states in Jervell and Lange-Nielsen syndrome (JLNS) patients (Gao Y et al. J Cardiovasc Dis Res. 2012;3:67-75; Vyas B et al. Am. J. Med. Genet. A. 2016;170:1510-9). Functional studies have demonstrated that p.R190Q disrupts KCNQ1 protein function, likely as a result of a trafficking defect, causing a reduction in the potassium current (Chouabe C et al. Cardiovasc. Res. 2000;45:971-80; Moretti A et al. N. Engl. J. Med. 2010;363:1397-409; Barsheshet A et al. Circulation. 2012;125:1988-96; Chen Z et al. Eur. Heart J. 2016;epub:ehw189). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Congenital long QT syndrome Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 30, 2022The p.Arg190Gln variant in KCNQ1 has been reported in at least 10 individuals with Long QT syndrome (LQTS) and segregated with disease in 6 affected individuals from 2 families (Wang 1996 PMID: 8528244, Wang 1999 PMID: 10376919, Chouabe 2000 PMID: 10728423, Barsheshet 2012 PMID: 22456477, Gao 2012 PMID: 22629021, Giudicessi 2012 PMID: 22949429, Ebrahim 2017 PMID: 28532774, Marschall 2019 PMID: 31737537, Westphal 2020 PMID: 32383558, Choi 2021 PMID: 34319147). It has also been identified in 1/113014 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 3117). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies support an impact on protein function (Wang 1999 PMID: 10376919, Chouabe 2000 PMID: 10728423, Barsheshet 2012 PMID: 22456477). Another variant involving this codon (p.Arg190Leu) has been identified in individuals with LQTS and is classified as likely pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PS4_Moderate, PM5, PP1_Moderate, PM2_Supporting, PP3, PS3_Moderate. -
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:8528244;PMID:9386136;PMID:10728423;PMID:11668638;PMID:14678125;PMID:15051636;PMID:15840476;PMID:19716085;PMID:19841300;PMID:10376919;PMID:17470695;PMID:9693036;PMID:22456477;PMID:22629021). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 17, 2024This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 190 of the KCNQ1 protein (p.Arg190Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 8528244, 10728423, 17470695, 20660394, 22629021). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg61Gln. ClinVar contains an entry for this variant (Variation ID: 3117). 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: 10376919, 10728423). For these reasons, this variant has been classified as Pathogenic. -
Cardiac arrhythmia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 26, 2019This missense variant replaces arginine with glutamine at codon 190 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 causes a loss of KCNQ1 channel activity (PMID: 10376919, 10728423, 20660394). This variant has been reported in individuals affected with long QT syndrome (PMID: 17470695, 19841300, 21350584, 22949429, 23075154, 8528244, 10728423, 20660394) and in individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 22629021, 27485560). This variant has been shown to segregate with disease in multiple families affected with long QT syndrome (PMID: 8528244, 10728423, 20660394). This variant has been identified in 1/249462 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
Pathogenic
0.90
CardioboostArm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
Cadd
Pathogenic
34
Dann
Pathogenic
1.0
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.8
D;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.99, 0.97
MutPred
0.91
.;Loss of methylation at R190 (P = 0.0273);.;
MVP
0.98
MPC
1.3
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.94
gMVP
0.96

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: rs120074178; hg19: chr11-2591949; API