rs199473394

Positions:

• chr11-2570685-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.535G>A​(p.Gly179Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,422 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G179A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 B:1 O:2
• Conservation: PhyloP100: 7.38

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2570686-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 378906.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 11-2570685-G-A is Pathogenic according to our data. Variant chr11-2570685-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570685-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.535G>A	p.Gly179Ser	missense_variant	3/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.535G>A	p.Gly179Ser	missense_variant	3/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.154G>A	p.Gly52Ser	missense_variant	3/16	1
KCNQ1	ENST00000496887.7	c.274G>A	p.Gly92Ser	missense_variant	4/16	5
KCNQ1	ENST00000646564.2	c.478-12750G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460218 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726498

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0482 Hom.: 842

Bravo AF: 0.0000189

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Benign:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	research	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jan 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 10, 2021	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 19, 2019	- -

Long QT syndrome Pathogenic:2 Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Pathogenic and reported on 07-18-2019 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR ) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 179 of the KCNQ1 protein (p.Gly179Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (LQTS) (PMID: 10973849, 15051636, 23392653, 27041150, 27831900, 28944242). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53063). 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, 29532034). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 16, 2023	The c.535G>A (p.Gly179Ser) variant in the KCNQ1 gene has been identified in heterozygous status in at least eight individuals affected with Long QT syndrome (LQTS) (PMID:10973849, 25845942, 27831900, 28438721, 19716085, 26318259, 26669661). This variant has also been reported in bi-allelic status in several (thirteen) families affected with Long QT syndrome (PMID: 27485560, 27041150,15051636, 28944242, 28438721, 28606196, 29684900, 23392653, 29033053), and found to segregate with disease in at least three families (PMID: 28944242, 28438721, 15051636). Homozygous and compound heterozygous individuals typically display more pronounced prolongation of the QT interval compared with heterozygous relatives who are often clinically asymptomatic or with modestly prolonged QT interval, suggesting incomplete penetrance and variable expressivity for the autosomal dominant form of LQTS associated with this variant. In vitro functional studies on HEK293 cells and X. laevis oocytes have shown that this variant exerts dominant negative effect on wild type protein and reduce cell surface expression, trafficking defects and severely low channel current (PMID: 29532034, 15051636). In-silico computational prediction tools suggest that the p.Gly179Ser variant may have deleterious effect on the protein function (REVEL score: 0.931). This variant is found to be absent in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 53063). Other missense substitutions affecting the same codon (p.Gly179Ala, p.Gly179Arg) have been interpreted as likely pathogenic by two ClinVar submitters (ClinVar ID: 2446426, 378906). Therefore, the c.535G>A (p.Gly179Ser) variant in the KCNQ1 gene is classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KCNQ1: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In vitro functional studies demonstrate loss of function with a trafficking defect and severely reduced cell surface expression (Huang et al., 2018); This variant is associated with the following publications: (PMID: 34505893, 25637381, 15051636, 25845942, 19716085, 23392653, 25935074, 27041150, 28944242, 28438721, 28606196, 29684900, 30571187, 10973849, 27485560, 29021305, 31785541, 31447099, 32383558, 27831900, 29532034) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 13, 2021	- -

Congenital long QT syndrome Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 15, 2019	The p.Gly179Ser variant in KCNQ1 has been reported in the heterozygous state in at least 3 individuals with autosomal dominant long QT syndrome (LQTS), one of whom had a more severe phenotype and carried a presumed pathogenic variant in another LQTS gene (Splawski 2000, Kapplinger 2009, Fernandes 2015, Natarajan 2016). It has also been reported in the homozygous or compound heterozygous state in 4 individuals with severe autosomal recessive LQTS (AR-LQTS) and segregated with AR-LQTS in 3 affected relatives from 2 families (Westenskow 2004, Giudicessi 2013, Vyas 2016, Bdier 2017). Individuals with AR-LQTS typically had a more severe phenotype with an earlier age of onset than heterozygotes, but none were reported to have hearing loss. Relatives of these individuals who were heterozygous carriers of this variant were often clinically asymptomatic or had modestly prolonged QT interval; however 1 heterozygous carrier experienced sudden cardiac death (Westenskow 2004, Giudicessi 2013, Bdier 2017), suggesting reduced penetrance and variable expressivity for the autosomal dominant form of LQTS associated with this variant. In vitro functional studies and computational prediction tools support an impact on protein function (Westenskow 2004, Huang 2018). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 53063) and was absent from large population studies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant and autosomal recessive LQTS. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP1_Moderate, PP3, PS3_Supporting, PS4_Supporting. -
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:10973849;PMID:15051636;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

KCNQ1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 29, 2024

The KCNQ1 c.535G>A variant is predicted to result in the amino acid substitution p.Gly179Ser. This variant has been reported in the heterozygous, compound heterozygous, and homozygous states in individuals and families with long QT syndrome, although heterozygous carriers have been described as asymptomatic (see, for example, Splawski et al. 2000. PubMed ID: 10973849; Westenskow et al. 2004. PubMed ID: 15051636; Al-Hassnan et al. 2017. PubMed ID: 28438721; Table S1, Westphal et al. 2020. PubMed ID: 32383558; Table S1, Schwartz et al. 2021. PubMed ID: 34505893). In vitro functional studies suggest this variant impacts protein function (Westenskow et al. 2004. PubMed ID: 15051636; Huang et al. 2018. PubMed ID: 29532034). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2020

The p.G179S pathogenic mutation (also known as c.535G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 535. The glycine at codon 179 is replaced by serine, an amino acid with similar properties. This alteration has been detected in the heterozygous, homozygous, and compound heterozygous state in numerous unrelated individuals with longQT syndrome (LQTS) (Splawski I, Circulation 2000 Sep; 102(10):1178-85; Kapplinger JD, Heart Rhythm 2009 Sep; 6(9):1297-303; Anderson HN, Pediatr Cardiol 2015 Oct; 36(7):1350-6; Fernandes M et al. Rev Port Cardiol, 2015 May;34:359.e1-5; Natarajan P et al. Sci Transl Med, 2016 11;8:364ra151; Al-Hassnan ZN et al. Heart Rhythm, 2017 08;14:1191-1199). The alteration has been reported to segregate with disease in multiple families, with homozygous and compound heterozygous individuals typically displaying more pronounced prolongation of the QT interval compared with heterozyous relatives (Westenskow P et al. Circulation, 2004 Apr;109:1834-41; Giudicessi JR et al. Circ Cardiovasc Genet, 2013 Apr;6:193-200; Vyas B et al. Am. J. Med. Genet. A, 2016 06;170:1510-9; Bdier AY et al. Mol Genet Genomic Med, 2017 Sep;5:592-601). Several functional studies indicate that this alteration results in a trafficking defect and reduced potassium current in heterologous expression systems (Westenskow P et al. Circulation, 2004 Apr;109:1834-41; Huang H et al. Sci Adv, 2018 03;4:eaar2631). 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 22, 2023

This missense variant replaces glycine with serine at codon 179 in the cytoplasmic linker region between transmembrane domains S2 and S3 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 protein trafficking defect and results in significantly reduced cell surface expression and channel current (PMID: 15051636, 29532034), as well as dominant negative effect on the wild type protein (PMID: 29532034). This variant has been reported in over ten heterozygous and biallelic individuals affected with long QT syndrome (PMID: 10973849, 15051636, 23392653, 25845942, 27041150, 27831900, 28606196, 28438721, 28944242, 29684900; Color data). Biallelic individuals showed severe long QT syndrome without hearing loss (PMID: 23392653, 27041150, 28944242, 29684900). This variant has been shown to cosegregate with long QT phenotype in multiple families (PMID: 15051636, 23392653, 28438721; Color data). This variant has not been identified 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	0.88
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.86, 0.86
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.93
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs199473394; hg19: chr11-2591915;