rs199472676

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PS4_ModerateBP5

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.217C>A (p.Pro73Thr) is a missense variant that causes substitution of proline with threonine at amino acid 73. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0002533, with 287 alleles / 1132988 total alleles in the European non-Finnish population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1 (PS4_Moderate; PMID:15840476, PMID:19716085, PMID:22949429, PMID:24606995, PMID:20851114). The variant has been reported to segregate with long QT syndrome 1 through a proband and 1 affected family member (PMID:26743238), which is not sufficient to meet PP1. This variant has been observed in 1 patient with an alternate molecular basis for disease (NM_000335.5(SCN5A):c.1231G>A (p.Val411Met)) with a phenotype that matches long QT syndrome 3 (BP5; PMID:28588847, PMID:23098067). This variant has also been observed in 1 patient with additional variants in KCNQ1 present both in cis (NM_000218.3(KCNQ1):c.502G>A (p.Gly168Arg)) and in trans (listed as p.Asp454Thrfs*7) providing an alternate molecular basis for disease (PMID:24667783), however, BP5 is only applicable when the phenotypes match another form of LQTS. The computational predictor REVEL gives a score of 0.566, 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 0.01 for donor gain, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.5 and does not strongly predict a damaging effect on KCNQ1 splicing. The Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29) was unable to generate a prediction of functional impact for this variant due to a limitation of the model and the unavailability of secondary structure at this residue (PMID:29021305), so neither PS3_Supporting nor BS3_Supporting was 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: PS4_Moderate, BP5. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA006724/MONDO:0100316/112

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:11B:2O:1

Conservation

PhyloP100: 1.34

Publications

12 publications found

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 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

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.217C>A	p.Pro73Thr	missense_variant	Exon 1 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9
KCNQ1	NM_001406836.1 link	c.217C>A	p.Pro73Thr	missense_variant	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1 link	c.217C>A	p.Pro73Thr	missense_variant	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1 link	c.-146C>A		5_prime_UTR_variant	Exon 1 of 17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 link	c.217C>A	p.Pro73Thr	missense_variant	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2		P51787-1

Frequencies

GnomAD3 genomes

AF:

0.0000859

AC:

AN:

151300

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000153

AC:

AN:

150334

AF XY:

0.000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000426

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000275

Gnomad OTH exome

AF:

0.000813

GnomAD4 exome

AF:

0.000215

AC:

291

AN:

1353216

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

141

AN XY:

671114

show subpopulations

African (AFR)

AF:

0.0000349

AC:

AN:

28668

American (AMR)

AF:

0.0000573

AC:

AN:

34916

Ashkenazi Jewish (ASJ)

AF:

0.0000427

AC:

AN:

23400

East Asian (EAS)

AF:

0.00

AC:

AN:

33146

South Asian (SAS)

AF:

0.00

AC:

AN:

74204

European-Finnish (FIN)

AF:

0.0000300

AC:

AN:

33312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4786

European-Non Finnish (NFE)

AF:

0.000260

AC:

277

AN:

1065168

Other (OTH)

AF:

0.000162

AC:

AN:

55616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000859

AC:

AN:

151300

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73910

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41310

American (AMR)

AF:

0.0000658

AC:

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67820

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.000117

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11Benign:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 11, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with LQTS (PMID: 15840476, 20851114, 23098067, 24606995, 26743238); Also reported in individuals who harbor an additional pathogenic variant that could explain their phenotype (PMID: 24667783, 29598884, 28588847); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24606995, 23098067, 19716085, 25351510, 22949429, 19862833, 19841300, 26633542, 20851114, 26986070, 28595573, 28588847, 28988457, 29197658, 29598884, 33181513, 31737537, 24667783, 15840476, 26743238, 22581653, 32048431, RidaM2023[Preprint], 37937776, 37449562) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Long QT syndrome 1

Uncertain:2

Oct 23, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Uncertain significance

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.217C>A (p.Pro73Thr) is a missense variant that causes substitution of proline with threonine at amino acid 73. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0002533, with 287 alleles / 1132988 total alleles in the European non-Finnish population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1 (PS4_Moderate; PMID: 15840476, PMID: 19716085, PMID: 22949429, PMID: 24606995, PMID: 20851114). The variant has been reported to segregate with long QT syndrome 1 through a proband and 1 affected family member (PMID: 26743238), which is not sufficient to meet PP1. This variant has been observed in 1 patient with an alternate molecular basis for disease (NM_000335.5(SCN5A):c.1231G>A (p.Val411Met)) with a phenotype that matches long QT syndrome 3 (BP5; PMID: 28588847, PMID: 23098067). This variant has also been observed in 1 patient with additional variants in KCNQ1 present both in cis (NM_000218.3(KCNQ1):c.502G>A (p.Gly168Arg)) and in trans (listed as p.Asp454Thrfs*7) providing an alternate molecular basis for disease (PMID: 24667783), however, BP5 is only applicable when the phenotypes match another form of LQTS. The computational predictor REVEL gives a score of 0.566, 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 0.01 for donor gain, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.5 and does not strongly predict a damaging effect on KCNQ1 splicing. The Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29) was unable to generate a prediction of functional impact for this variant due to a limitation of the model and the unavailability of secondary structure at this residue (PMID: 29021305), so neither PS3_Supporting nor BS3_Supporting was 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: PS4_Moderate, BP5. (VCEP specifications version 1.0.0; date of approval 03/04/2025). -

Cardiovascular phenotype

Uncertain:1Benign:1

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4_sup,PM1_sup,PP2,BP2,BP4 -

Oct 21, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1

Uncertain:1

Feb 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Short QT syndrome type 2

Uncertain:1

Oct 23, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Uncertain:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the KCNQ1 protein (p.Pro73Thr). This variant is present in population databases (rs199472676, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (PMID: 15840476, 19716085, 22949429, 24606995, 24667783, 26743238, 28588847). ClinVar contains an entry for this variant (Variation ID: 53031). 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. -

not specified

Benign:1

Feb 16, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KCNQ1 c.217C>A (p.Pro73Thr) results in a non-conservative amino acid change in 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 0.00015 in 150334 control chromosomes, predominantly at a frequency of 0.00028 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Long QT Syndrome phenotype (8.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.217C>A has been reported in the literature in individuals affected with Long QT Syndrome (Example: Tester_2005, Kapa_2009, Kapplinger_2009, Marschall_2019, Millat_2011) etc . These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (KCNH2 c.87C>A, p.Phe29Leu; SCN5A c.1231G>A, p.Val411Met; KCNQ1 c.502G>A, P.Gly168Arg) (Mullertz_2018, Magnusson_2017, Riuro_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

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:15840476;PMID:19716085;PMID:19841300). 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

0.079

CardioboostArm

Benign

0.012

BayesDel_addAF

Benign

0.0080

BayesDel_noAF

Uncertain

0.080

CADD

Benign

7.3

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.30

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.39

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

1.5

PhyloP100

1.3

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.79

REVEL

Uncertain

0.57

Sift

Benign

0.037

Sift4G

Benign

0.56

Polyphen

0.0010

Vest4

0.16

MutPred

0.75

Gain of phosphorylation at P73 (P = 0.0102);

MVP

0.80

MPC

1.3

ClinPred

0.036

GERP RS

-0.73

PromoterAI

0.052

Neutral

(source)

Varity_R

0.033

gMVP

0.22

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over