rs179489

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.502G>A(p.Gly168Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,508 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

Frequency

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

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 9.44

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]

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PS1

Transcript NM_000218.3 (KCNQ1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 11-2570652-G-A is Pathogenic according to our data. Variant chr11-2570652-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570652-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.502G>A	p.Gly168Arg	missense_variant	3/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.502G>A	p.Gly168Arg	missense_variant	3/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.121G>A	p.Gly41Arg	missense_variant	3/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.241G>A	p.Gly81Arg	missense_variant	4/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.478-12783G>A		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000120

AC:

AN:

249646

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1460328

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726574

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital long QT syndrome

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 02, 2023	- -
not provided, no classification provided	literature only	Cardiovascular 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:20186784;PMID:9693036;PMID:12402336;PMID:10973849;PMID:19716085;PMID:15051636;PMID:17905336;PMID:15840476;PMID:14678125;PMID:12566525;PMID:19841300;PMID:9386136). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely pathogenic, no assertion criteria provided	research	Genetics and Genomics Program, Sidra Medicine	-	The c.502G>A missense variant in KCNQ1 is reported in ClinVar as pathogenic (SCV000064963) and is absent from gnomAD, indicating rarity (PM2). In silico predictions support its deleterious effect, with PolyPhen predicting it as probably damaging and SIFT as deleterious (PP3). The variant is located in a mutational hot spot, which is suggestive of pathogenicity (PM1), and it was inherited from the affected mother, further supporting its clinical relevance. Despite some conflicting evidence (BP1), the overall data supports a likely pathogenic classification (ACMG codes: PM1, PM2, PP3, PP5, BP1). -

not provided

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 13, 2013	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.Gly168Arg The Gly168Arg mutation in KCNQ1 has been reported multiple times in association with autosomal dominant long QT syndrome, and in vitro analysis has shown it to cause complete loss of potassium channel function. Strong segregation data comes from Beery et al. (2003). Gly168Arg segregated with disease in all 7 affected members of an LQTS family (from 4 generations). Gly168Arg is a chemically nonconservative amino acid change. It substitutes the smallest, nonpolar amino acid Glycine, which lacks a carbon side chain, with the bulkier positively-charged amino acid side chain of Arginine. The Glycine at position 168 is highly conserved across species. In silico analysis predicts the variant to be “probably damaging” (PolyPhen) and “deleterious” (SIFT). This variant has been reported in over 32 unrelated individuals with LQTS. It is not present in 1800 reported controls, nor in ~6450 individuals in the NHLBI ESP project. Donger et al. (1997) found this mutation in 5 individuals in one French family affected by LQT1. Four of these family members, as a group, had a mean QTc of 477+24 msec, while the fifth died suddenly before age 40. The Gly168Arg mutation was absent in 200 control alleles. Splawski et al. (2000) reported this variant in 7 out of 262 unrelated European and American probands with LQTS; it was absent from more than 400 control alleles. Jongbloed et al. (2002) identified 1 Gly168Arg variant among 32 Dutch and Belgian index patients; they report that a variant was classified as pathogenic if it “segregated with the disease in the family” and was absent from 100 control chromosomes. Van Langen et al. (2003) found Gly168Arg in 1 out of 40 consecutive, unrelated LQTS patients from the Netherlands and Belgium; it was absent from 100 control alleles. Westenskow et al. (2004) reported a family affected by 2 LQTS variants, of which Gly168Arg was one. The family member carrying Gly168Arg alone had a QTc in the normal range (440) and no history of syncope, while two family members who carried both variants had prolonged QTc (480 and 510) and syncope. Therefore, this particular study does not add convincing clinical evidence of pathogenicity. However, it does include in-vitro biophysical data, showing that Gly168Arg causes complete loss of channel function. Tester et al. (2005) reported the variant in 2 of 541 consecutive, unrelated patients referred to Mayo Clinic’s Sudden Death Genomics Laboratory for LQTS genetic testing. Moss et al. (2007) did an outcome study of 600 KCNQ1-variant-carrying patients (from 101 families) included in the US portion of the International LQTS Registry (n=425), the Netherlands’ LQTS Registry (n=93), and the Japanese LQTS Registry (n=82), and 44 of these 600 patients had the Gly168Arg variant. This made Gly168Arg the second-most common variant represented in the study. Chung et al. (2007) found it in 1 of 84 consecutive LQTS index cases tested in New Zealand (but not in 100 control chromosomes); she had a QTc of 500 msec, a history of syncope, and a first-degree relative who had died suddenly. Kapplinger et al. (2009) reported the Gly168Arg variant in 15 out of 2500 unrelated individuals diagnosed with LQTS and consecutively referred for genetic testing through PGxHealth; they did not find the variant in more than 2,600 reference alleles from individuals of diverse ethnicity (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). The variant has also been reported by Marquez et al. (2006) in a homozygous state in two affected siblings, from a Mexican family, diagnosed with Jervell and Lange-Nielsen Syndrome—a recessive form of LQTS accompanied by dea -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2020	Observed in multiple unrelated individuals with LQTS referred for genetic testing at GeneDx and in the published literature (for examples, see Splawski et al., 1998; Jongbloed et al., 2002; Kapplinger et al., 2009; Yoshinaga et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate G168R (nucleotide change not specified) impairs potassium ion channel function (Westenskow et al., 2004; Jons et al., 2011; Barshesshet et al, 2012); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 53052; ClinVar); This variant is associated with the following publications: (PMID: 14678125, 26318259, 10973849, 25479336, 14531214, 12402336, 15840476, 17905336, 19716085, 24103226, 26681611, 19490272, 23995044, 21185501, 20186784, 17091796, 24667783, 27485560, 27041150, 12566525, 29952348, 17470695, 23130128, 22949429, 9693036, 19841300, 23124029, 29330128, 15051636, 22456477, 21451124, 31737537, 34319147, 33256261, 32665702, 34135346, 33087929) -

Long QT syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 168 of the KCNQ1 protein (p.Gly168Arg). This variant is present in population databases (rs179489, gnomAD 0.003%). This missense change has been observed in individuals with long QT syndrome (PMID: 9693036, 10973849, 17905336, 19841300, 23130128). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53052). 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: 19490272). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 08, 2020	Variant summary: KCNQ1 c.502G>A (p.Gly168Arg) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 252834 control chromosomes. c.502G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (e.g. Splawski_1998, Beery_2003, Chung_2007, Summers_2010, Giudicessi_2012), including multi-generational families in which the variant segregated with disease. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence indicating that the variant alters potassium channel activity (e.g. Barsheshet_2012, Jons_2011). Four 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. Based on the evidence outlined above, the variant was classified as pathogenic. -

Long QT syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Jan 01, 2013

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2021

The p.G168R pathogenic mutation (also known as c.502G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 502. The glycine at codon 168 is replaced by arginine, an amino acid with dissimilar properties, and is located in the S2 transmembrane region of the protein. This alteration, and another nucleotide substitution resulting in the same amino acid change (c.502G>C), has been detected in multiple unrelated, heterozygous individuals reported to have long QT syndrome (LQTS), has been reported to segregate with LQTS in multiple families, and has been reported in the homozygous and compound heterozygous states in individuals with Jervell and Lange-Nielsen syndrome (Donger C et al. Circulation. 1997;96(9):2778-81; Splawski et al. Genomics. 1998;51(1):86-97; Splawski I et al. Circulation. 2000;102(10):1178-85; Márquez MF et al. Arch Cardiol Mex. 2006;76(3):257-62; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Summers KM et al. Am J Med Genet. 2010;152A(3):613-21; Vyas B. Am. J Med Genet A. 2016;170(6):1510-9; Sato A et al. Int Heart J. 2019 Sep;60(5):1206-1210; Lorca R et al. J Clin Med. 2020 Nov;9(12)). This alteration has been reported to result in loss of ion channel function in an in vitro assay (Westenskow P et al. Circulation. 2004;109(15):1834-41). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 21, 2023

This missense variant replaces glycine with arginine at codon 168 in the transmembrane domain 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 changes potassium channel current (PMID: 21451124, 22456477). This variant has been reported in multiple individuals affected with long QT syndrome (PMID: 19490272, 19716085, 26318259, 26681611, 27921062, 28794082, 29952348, 14531214, 20186784). It has been shown that this variant segregates with long QT syndrome in numerous individuals from multiple families (PMID: 14531214, 20186784, 21451124, 26318259). This variant has also been reported in the homozygous state in a few individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 17091796, 27041150, 27485560). This variant has been identified in 3/249646 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

.;D;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.0

D;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.021

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.98, 0.95

MutPred

0.90

.;Gain of methylation at G168 (P = 0.0225);.;

MVP

0.98

MPC

2.5

ClinPred

0.99

GERP RS

4.4

Varity_R

0.96

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over