rs199472781

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5BP4

The NM_000218.3(KCNQ1):c.1352G>A(p.Arg451Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. R451W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:3O:1

Conservation

PhyloP100: 1.71

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 Uncertain_significance. Variant got 1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2588812-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.27512392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.1352G>A	p.Arg451Gln	missense_variant	Exon 10 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 link	c.1352G>A	p.Arg451Gln	missense_variant	Exon 10 of 16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.971G>A	p.Arg324Gln	missense_variant	Exon 10 of 16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.995G>A	p.Arg332Gln	missense_variant	Exon 10 of 16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.812G>A	p.Arg271Gln	missense_variant	Exon 5 of 11			ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

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:

0.000479

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

249856

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135358

show subpopulations

Gnomad AFR exome

AF:

0.000435

Gnomad AMR exome

AF:

0.0000290

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1460900

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000171

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000603

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:

0.000479

Alfa

AF:

0.000176

Hom.:

Bravo

AF:

0.000215

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:2Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 20, 2023

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 arginine with glutamine at codon 451 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). An experimental functional study using transfected CHO cells has shown that this variant causes a reduction in current (PMID: 36898499). A zebrafish model for this variant showed lower heart rate and time interval between peak maximum upstroke velocity and time for repolarization (PMID: 36898499). This variant has been reported in an individual affected with long QT syndrome (PMID: 15234419). This variant has been identified in 13/281216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2Other:1

Oct 24, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the KCNQ1 gene. The R451Q variant has been previously reported in one Japanese individual in association with LQTS (Shimizu et al., 2004), and has been observed in one other individual referred for LQTS genetic testing at GeneDx. However, no segregation data was available for either of these individuals. Additionally, R451Q was found in one African American individual from a cohort of ostensibly healthy control individuals (Ackerman et al., 2003; Kapa et al., 2009; Giudicessi et al., 2012), although a follow-up cardiac evaluation was not reported. Nevertheless, the R451Q variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, R451Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, however, Glutamine is tolerated at this position in at least one mammalian species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Finally, a missense variant at the same residue (R451W) has been reported in HGMD in association with LQTS (Stenson et al., 2014), however, the clinical significance of this variant has not been definitely determined. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

May 02, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 in the following publications (PMID:14661677;PMID:15234419;PMID:19841300;PMID:22378279). -

Long QT syndrome 1

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Atrial fibrillation, familial, 3

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jervell and Lange-Nielsen syndrome 1

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiac arrhythmia

Uncertain:1

May 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Short QT syndrome type 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype

Benign:1

Jun 07, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.40

T;.;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.72

T;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Pathogenic

0.93

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.93

N;.;N

REVEL

Uncertain

0.62

Sift

Benign

0.41

T;.;T

Sift4G

Benign

0.61

T;.;T

Polyphen

0.97

D;.;P

Vest4

0.76

MVP

0.90

MPC

0.43

ClinPred

0.029

GERP RS

2.9

Varity_R

0.046

gMVP

0.48

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

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