11-2570733-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5PP3_StrongPP5

The NM_000218.3(KCNQ1):c.583C>T(p.Arg195Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,611,616 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. R195Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6O:1

Conservation

PhyloP100: 1.73

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 Likely_pathogenic. Variant got 7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2570734-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 11-2570733-C-T is Pathogenic according to our data. Variant chr11-2570733-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67087.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=6, not_provided=1}. Variant chr11-2570733-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.583C>T	p.Arg195Trp	missense_variant	Exon 3 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.583C>T	p.Arg195Trp	missense_variant	Exon 3 of 16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.202C>T	p.Arg68Trp	missense_variant	Exon 3 of 16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.322C>T	p.Arg108Trp	missense_variant	Exon 4 of 16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.478-12702C>T		intron_variant	Intron 2 of 10			ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249190

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135144

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1459446

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726144

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000143

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Pathogenic:1Uncertain:2

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Jun 09, 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 arginine with tryptophan at codon 195 of the KCNQ1 protein. This variant is found within the highly conserved cytoplasmic linker region (a.a. 169-196). Rare non-truncating 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 increases channel current in Xenopus laevis oocytes (PMID: 25786344), while another study using a different expression system demonstrated that this variant causes reductions in cell surface expression, total expression, and trafficking efficiency compared to the wild type (PMID: 33600800). This variant has been reported in an individual affected with long QT syndrome (PMID: 35703482) and in two individuals referred for long QT syndrome testing (PMID: 19716085). It has also been reported in an individual affected with early-onset lone atrial fibrillation (PMID: 24144883, 25786344). This variant has been identified in 8/280548 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. -

Oct 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 195 of the KCNQ1 protein (p.Arg195Trp). This variant is present in population databases (rs150172393, gnomAD 0.006%). This missense change has been observed in individuals with lone atrial fibrilliation and/or prolonged QT interval (PMID: 19716085, 25786344, 35703482; internal data). ClinVar contains an entry for this variant (Variation ID: 67087). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 24947509, 25786344, 33600800). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Atrial fibrillation

Pathogenic:1

Mar 01, 2024

Lildballe Lab, Aarhus University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM1(m), PP2(sup), PM2(sup), PP3(m) -

not specified

Uncertain:1

Feb 15, 2024

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.583C>T (p.Arg195Trp) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249190 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.583C>T has been reported in the literature in individuals affected with long-QT syndrome or atrial fibrillation (Kapplinger_2009, Olesen_2013, Steffensen_2015, Diebold_2020, Saat_2022). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least two publications report experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Steffensen_2015, Huang_2021). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 32048431, 33600800, 19716085, 24190995, 24144883, 35703482, 25786344). ClinVar contains an entry for this variant (Variation ID: 67087). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Dec 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R195W variant (also known as c.583C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 583. The arginine at codon 195 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a long QT syndrome clinical genetic testing cohort, an early-onset atrial fibrillation cohort, and an exome cohort, often with limited clinical detail (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Olesen MS et al. Heart Rhythm, 2014 Feb;11:246-51; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). In vitro studies have suggested that this mutant enhances the channel activity and reduces protein cell-surface expression; however, additional evidence is needed to confirm these findings. (Steffensen AB et al. J. Cardiovasc. Electrophysiol., 2015 Jul;26:715-23; Huang H et al. J Biol Chem. 2021 Feb;296:100423). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Dec 19, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 195 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). A functional study has shown that this variant increases channel current while has no effect on the subcellular localization of the channel protein (PMID: 25786344). This variant has been reported in an individual affected with long QT syndrome (PMID: 35703482) and in two individuals referred for long QT syndrome testing (PMID: 19716085). It has also been reported in an individual affected with early-onset lone atrial fibrillation (PMID: 24144883, 25786344). This variant has been identified in 8/280548 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). 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

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.77

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.0

.;M;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.2

D;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.91, 0.91

MVP

0.97

MPC

1.2

ClinPred

0.97

GERP RS

1.1

Varity_R

0.91

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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