rs199472813

Variant names:

• chr11-2778011-G-A
• rs199472813
• NM_000218.3:c.1768G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2778011-G-A
• chr11-2778011-G-C
• chr11-2778011-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PP2 PP3_Moderate PP5

The NM_000218.3(KCNQ1):​c.1768G>A​(p.Ala590Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,536 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A590P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2 O:1
• Conservation: PhyloP100: 2.53
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000218.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• PP5: Variant 11-2778011-G-A is Pathogenic according to our data. Variant chr11-2778011-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53015.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1768G>A	p.Ala590Thr	missense_variant	Exon 15 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1768G>A	p.Ala590Thr	missense_variant	Exon 15 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152152 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250944 AF XY: 0.00000737

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 FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461384 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727008

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00000904 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 1 Pathogenic:2

Jan 13, 2022

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1 Uncertain:1

Mar 07, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with sinus bradycardia and LQTS or suspected LQTS; of note, one of the probands with a prolonged QTc was homozygous for this variant and had normal hearing (PMID: 14998624, 15840476, 19841300, 28532774, 28491806, 32421437); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19841300, 34505893, 31565860, 32421437, 17329209, 15840476, 22949429, 17329207, 18174212, 19825999, 19322600, 16623272, 28491806, 28532774, 24713462, 32048431, 31589614, 14998624, Bora[article]2023, 38657442, 38540378) -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ1: PM1, PM2, PS3:Moderate, PS4:Moderate, PP1 -

Long QT syndrome Pathogenic:1

Sep 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 590 of the KCNQ1 protein (p.Ala590Thr). This variant is present in population databases (rs199472813, gnomAD 0.004%). This missense change has been observed in individuals with definite or suspected long QT syndrome (PMID: 14998624, 22949429, 23130128, 24713462, 28491806). ClinVar contains an entry for this variant (Variation ID: 53015). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 24713462). For these reasons, this variant has been classified as Pathogenic. -

Cardiac arrhythmia Pathogenic:1

Feb 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 590 of the KCNQ1 protein. This variant is found within a highly conserved region (a.a.585-607) of C-terminal cytoplasmic coiled-coil domain. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant may adversely affect channel trafficking to the cell surface and function (PMID: 24713462). This variant has been reported in over ten unrelated individuals affected with long QT syndrome (PMID: 14998624, 15840476, 16623272, 19841300, 23130128, 24713462, 28491806, 28532774, 32421437, 32893267, 34395343, 37597120, 37901857). The variant has been observed in biallelic state in two of these individuals, who showed severe phenotypes but no hearing loss (PMID: 28491806, 37597120). This variant has been identified in 3/282306 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not specified Uncertain:1

Nov 13, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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.Ala590Thr Based on the data reviewed below we consider it a variant of uncertain significance, likely disease causing. The variant has been seen in one case of long QT, another case of possible neonatal long QT, and one case of drug-induced long QT. There is no segregation data available. Lupoglazoff et al (2004) first reported this variant in their French cohort. They observed it in a neonate with long QT syndrome. The patient was a male who presented with neonatal bradycardia and a QTc of 460 ms. At follow-up at 6 years of age he was asymptomatic. They note that the variant was inherited from the mother but no phenotypic data on the mother is provided. I had our peds EP team review this case and they felt the data reported was perhaps suspicious for a diagnosis of long QT but did not strongly support it. Couderc et al (2012) included a patient with this variant in an analysis of QT-RR relationship in patients with long QT, however the data for that study was pulled from a French database so this may be the same case that was reported by Lupoglazoff et all (2004). The variant was also reported in a compendium of variants found in Dr. Ackerman's research lab (Tester et al 2005). The variant was observed in 1 of 541 individuals with "suspected" long QT syndrome enrolled in Dr. Ackerman's studies. Individual phenotypic data was not reported, however sufficient data was available to calculate a Schwartz score in 77% of cases. A Schwartz score ? 4 (indicating high confidence in the diagnosis) was present 29% of the overall cohort and 40% of individuals with a KCNQ1 variant. The overall yield was 50%, compared to 70% in studies where all the patients had a firmer diagnosis of long QT syndrome. Taken together these data suggest that a proportion of patients in this study did not in fact have long QT syndrome. However, the same group later included a case with this variant in two other publications and noted that only cases with a strong diagnosis (Schwartz score ? 4 or QTc ? 480 ms were included) (Kapa et al 2009, Giudicessi et al 2012). Given ascertainment methods for the three papers it is likely they are all referring to the same case. I suspect this case was also included in a paper by Goldenberg et al (2011) and one by Barsheshet et al (2012) as Dr. Ackerman is a co-author on both and cases from his cohort were included. Goldenberg et al (2011) list three individuals with p.Ala590Thr, however the study included people with long QT and genotype-positive, phenotype-negative relatives, and it is unclear whether those three individuals had phenotype. Novotny et al (2006) reported the variant in a study on drug-induced long QT, though unfortunately the paper is in Czech. Using google translate it looks like they observed the variant in male with a QTc of 450 ms while on venlafixine (Effexor). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The alanine at codon 590 is conserved across mammals but is a serine in fugu and c elegans. Other variants have been reported in association with disease at nearby codons (p.Thr587Met, p.Gly589Asp, p.Arg591Cys, p.Arg591His, p.Arg594Gln, p.Arg594Pro, p.Glu596Lys). In total the variant has not been seen in ~8100 published controls and individuals from publicly available population datasets. There is no variation at codon 590 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6500 Caucasian and African American individuals (as of February 27th, 2013). The variant is in 1000 genomes and dbSNP (rs199472813) but only in reference to the reports with long QT syndrome.The variant was not observed in the followin -

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:14998624;PMID:15840476;PMID:16623272;PMID:17329209;PMID:19841300;PMID:17329207). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
CardioboostArm	Uncertain	0.86
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.;.;.
PhyloP100		2.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N;.;N;.
REVEL	Pathogenic	0.82
Sift	Benign	0.14	T;.;T;.
Sift4G	Benign	0.17	T;.;T;.
Polyphen		0.89	P;.;P;.
Vest4		0.88
MutPred		0.74		Gain of helix (P = 0.062);.;.;.;
MVP		0.96
MPC		1.0
ClinPred		0.83	D
GERP RS		3.1
PromoterAI		0.020	Neutral
Varity_R		0.18
gMVP		0.95
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs199472813; hg19: chr11-2799241; COSMIC: COSV108030835;