rs147445322

Variant names:

• chr11-2847803-G-A
• rs147445322
• NM_000218.3:c.1831G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2847803-G-A
• chr11-2847803-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.1831G>A is a missense variant that causes replacement of aspartic acid with asparagine at position 611. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001289, with 7/54310 in the Admixed American population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 but higher than the PM2_Supporting threshold of <0.00001, so neither criterion was met. This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1, however, two probands lacked the required phenotype details for inclusion in PS4_Supporting, so this code is not yet met (PMID:19716085, PMID:19862833, PMID:22727609, PMID:33614747). This variant has been detected in at least 1 individual with Jervell and Lange-Nielsen syndrome who had profound congenital deafness but only a borderline QTc interval of 446 ms, with the variant present in a compound heterozygous state, confirmed in trans with the NM_000218.3:c.546C>A (p.Ser182Arg) variant, which has not yet been classified by the ClinGen Potassium Channel Arrhythmia VCEP (PMID:27917693). The computational predictor REVEL gives a score of 0.593, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing. The variant does not have a predicted impact on KCNQ1 function in the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), due to a limitation of the model (PMID:29021305), so PS3_Supporting is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: None. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA006476/MONDO:0100316/112

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:12 B:1 O:1
• Conservation: PhyloP100: 4.89
• Publications: 17 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-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1831G>A	p.Asp611Asn	missense_variant	Exon 16 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1831G>A	p.Asp611Asn	missense_variant	Exon 16 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000717 AC: 13 AN: 181208 AF XY: 0.0000617

Gnomad AFR exome AF: 0.0000917

Gnomad AMR exome AF: 0.000108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000812

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000761 AC: 108 AN: 1419094 Hom.: 0 Cov.: 31 AF XY: 0.0000755 AC XY: 53 AN XY: 702052

African (AFR) AF: 0.0000307 AC: 1 AN: 32596

American (AMR) AF: 0.000154 AC: 6 AN: 39010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.0000534 AC: 2 AN: 37424

South Asian (SAS) AF: 0.0000866 AC: 7 AN: 80826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.0000807 AC: 88 AN: 1089980

Other (OTH) AF: 0.0000681 AC: 4 AN: 58732

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74450

African (AFR) AF: 0.0000482 AC: 2 AN: 41532

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000841 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000117 AC: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:12 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Long QT syndrome Uncertain:4 Benign:1

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 611 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 22727609, 33614747), in an individual referred for long QT syndrome test (PMID: 19716085), and in an individual suspected of having Jervell and Lange-Nielsen Syndrome (27917693). It has also been reported in an individual among exome sequencing participants not selected for cardiovascular disorders (PMID: 23861362) and in another two individuals with normal QTc internal (PMID: 26159999, 27917693). This variant has been identified in 17/212554 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PM2, PM5 -

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 611 of the KCNQ1 protein (p.Asp611Asn). This variant is present in population databases (rs147445322, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Jervell and Lang-Nielsen syndrome and/or clinical features of long QT syndrome (PMID: 19716085, 22727609, 25554238, 27917693, 30530868). ClinVar contains an entry for this variant (Variation ID: 67059). 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 not expected to disrupt KCNQ1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Long QT syndrome 1 Pathogenic:1 Uncertain:1

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2025

ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_000218.3(KCNQ1):c.1831G>A is a missense variant that causes replacement of aspartic acid with asparagine at position 611. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001289, with 7/54310 in the Admixed American population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 but higher than the PM2_Supporting threshold of <0.00001, so neither criterion was met. This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1, however, two probands lacked the required phenotype details for inclusion in PS4_Supporting, so this code is not yet met (PMID: 19716085, PMID: 19862833, PMID: 22727609, PMID: 33614747). This variant has been detected in at least 1 individual with Jervell and Lange-Nielsen syndrome who had profound congenital deafness but only a borderline QTc interval of 446 ms, with the variant present in a compound heterozygous state, confirmed in trans with the NM_000218.3:c.546C>A (p.Ser182Arg) variant, which has not yet been classified by the ClinGen Potassium Channel Arrhythmia VCEP (PMID: 27917693). The computational predictor REVEL gives a score of 0.593, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing. The variant does not have a predicted impact on KCNQ1 function in the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), due to a limitation of the model (PMID: 29021305), so PS3_Supporting is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: None. (VCEP specifications version 1.0.0; date of approval 03/04/2025). -

not specified Uncertain:2

Feb 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp611Asn variant in KCNQ1 has been reported in 3 individuals with Long QT syndrome (Andrsova 2012, Hedley 2009, Kapplinger 2009). It was also identified in 1 child with congenital profound hearing loss and a borderline QTc of 446 ms ec who had a second VUS in KCNQ1 in trans. The variant was found in the heterozy gous state in the child's unaffected mother (Wang 2017). In another study this variant was found in a heterozygous individual whose mean QTc interval was not s tatistically different than the mean QTc interval observed in 6061 Danish contro l individuals that were negative for the variant (Ghouse 2015). This variant ha s been identified in several populations by the Genome Aggregation Database with the highest allele frequency of 10/86082 European chromosomes (gnomAD, http://g nomad.broadinstitute.org/; dbSNP rs147445322) and is reported in ClinVar (Variat ion ID: 67059) by several laboratories or studies. Although the variant has been seen in unaffected individuals and in the general population, we cannot rule ou t a causative role due to reduced penetrance and variable expressivity that has been noted in some long QT families. Computational prediction tools and conserva tion analysis do not provide strong support for or against an impact to the prot ein. In summary, due its presence in both affected and unaffected individuals, l imited familial segregation data, and its frequency in the general population, t he clinical significance of the p.Asp611Asn variant is uncertain. ACMG/AMP Crite ria applied: None. -

Jul 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNQ1 c.1831G>A (p.Asp611Asn) results in a conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal (IPR013821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 181208 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in KCNQ1 causing Long QT Syndrome (7.2e-05 vs 0.0001), allowing no conclusion about variant significance. c.1831G>A has been reported in the literature in individuals affected with Long QT Syndrome or related phenotypes (Kapplinger_2009, Thauvin-Robinet_2019, Andrsova_2012, Tse_2021, Kwok_2018, Illikova_2015), although one publication found no significant difference in electrocardiogram results between a carrier and non-carriers of the variant (Ghouse_2015). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 26159999, 27917693, 31019283, 22727609, 33614747, 30530868, 25554238). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2

Jan 24, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported multiple times in association with LQTS or sudden cardiac arrest, though many publications lack patient-specific data (PMID: 19716085, 22727609, 25554238, 28749187, 30530868, 29884292); Reported in a Danish cohort screened for LQTS variants where QTc intervals in carriers were not statistically different compared with non-carriers (PMID: 26159999); Reported in a 6-year-old Chinese proband with congential profound deafness and QTc of 446. He also harbored a second missense variant in trans in the KCNQ1 gene. The p.(D611N) variant was inherited from his mother with normal hearing and a normal QTc interval (PMID: 27917693); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 22727609, 23861362, 28749187, 22378279, 19862833, 25554238, 29197658, 26633542, 25854863, 30530868, 29884292, 31019283, 32048431, 33614747, 19716085, 26159999, 27917693) -

Oct 20, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KCNQ1-related disorder Uncertain:1

Mar 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KCNQ1 c.1831G>A variant is predicted to result in the amino acid substitution p.Asp611Asn. This variant has been reported in individuals with long QT syndrome (Kapplinger et al. 2009. PubMed ID: 19716085; Hedley et al. 2009. PubMed ID: 19862833). Additionally, this variant has been reported compound heterozygous in a patient with severe hearing loss (Wang et al. 2016. PubMed ID: 27917693). One publication found no difference in QT intervals, syncopy, or morbidity in carriers versus non-carriers (Ghouse et al. 2015. PubMed ID: 26159999). This variant is reported in 0.010% of alleles in individuals of African, European (non-Finnish) and Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1

Oct 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1831G>A (p.D611N) alteration is located in exon 16 (coding exon 16) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 1831, causing the aspartic acid (D) at amino acid position 611 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Jul 18, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 611 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 22727609), in an individual suspected to be affected with long QT syndrome (PMID: 19716085), and in an individual suspected of having Jervell and Lange-Nielsen Syndrome (PMID: 27917693). It has also been reported in individuals without diagnoses of KCNQ1-related disorders (PMID: 23861362, 26159999, 27917693). This variant has been identified in 17/212554 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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:19716085;PMID:19862833;PMID:22378279). 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	0.093
CardioboostArm	Benign	0.00016
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Benign	-0.0074
Eigen_PC	Benign	0.0049
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.99	L;.;.
PhyloP100		4.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.53	N;N;.
REVEL	Uncertain	0.59
Sift	Benign	0.19	T;T;.
Sift4G	Benign	0.23	T;T;.
Polyphen		0.94	P;.;.
Vest4		0.76
MVP		0.95
MPC		0.38
ClinPred		0.034	T
GERP RS		2.9
Varity_R		0.52
gMVP		0.82
Mutation Taster		=21/79	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs147445322; hg19: chr11-2869033;