11-2570724-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate

The NM_000218.3(KCNQ1):c.574C>T(p.Arg192Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,611,772 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.70

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 6 ACMG points.

PM1

In a helix (size 6) in uniprot entity KCNQ1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000218.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2570725-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.574C>T	p.Arg192Cys	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.574C>T	p.Arg192Cys	missense_variant	Exon 3 of 16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.193C>T	p.Arg65Cys	missense_variant	Exon 3 of 16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 4 of 16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.478-12711C>T		intron_variant	Intron 2 of 10			ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000401

AC:

AN:

249252

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000490

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1459584

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000391

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:2

Apr 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 192 of the KCNQ1 protein (p.Arg192Cys). This variant is present in population databases (rs775059928, gnomAD 0.05%). This missense change has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 22629021, 23631430, 28606196, 28704380). ClinVar contains an entry for this variant (Variation ID: 578178). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 24947509, 30571187). 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. -

May 17, 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 cysteine at codon 192 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). A functional study has shown that the current of the mutant channel was significantly decreased upon PIP2 injection, indicating an impaired functional interaction with PIP2 (PMID: 24947509). This variant has been reported in one individual affected with long QT syndrome (PMID: 28606196), one individual with Romano-Ward syndrome (PMID: 22629021), one individual with suspected long QT syndrome (PMID: 23631430), and one case with sudden unexpected death syndrome (PMID: 28704380). This variant has been identified in 11/280628 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. -

not specified

Uncertain:1

Sep 12, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg192Cys variant in KCNQ1 has been reported in 1 heterozygous individual and 2 compound heterozygous individuals with long QT syndrome (LQTS), and one case with sudden death (Gao 2012, Lieve 2013, McLeod 2017, Suktitipat 2017). None of the compound heterozygous individuals had hearing loss. This variant has been identified in 0.05% (9/18834) of East Asian chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org). Computational prediction tools and cons ervation analysis suggest that the p.Arg192Cys variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, while there is some suspicion for a pathogenic role, the clinical signif icance of the p.Arg192Cys variant is uncertain. ACMG/AMP criteria applied: PS4_S upporting, PM2_Supporting, PP3. -

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

Nov 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Dec 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R192C variant (also known as c.574C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 574. The arginine at codon 192 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in conjunction with a KCNE1 variant and in trans with KCNQ1 c.1032G>A in an individual with Romano Ward syndrome; this variant was also identified in the proband's unaffected mother (Gao Y et al. J Cardiovasc Dis Res, 2012 Apr;3:67-75). This variant was identified in a long QT syndrome (LQTS) cohort (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61), in a sudden death victim in conjunction with a variant in DSP (Suktitipat B et al. PLoS ONE, 2017 Jul;12:e0180056), and in an individual with LQTS in conjunction with KCNQ1 p.G179S (McLeod KA et al. Cardiol Young, 2017 Sep;27:1271-1279). Function studies in Xenopus oocytes demonstrated an increased current, whereas studies in CHO cells demonstrated a reduced current (Eckey K et al. J. Biol. Chem., 2014 Aug;289:22749-58; Vanoye CG et al. Circ Genom Precis Med, 2018 11;11:e002345). 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

Apr 24, 2023

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 cysteine at codon 192 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). A functional study has shown that the current of the mutant channel was significantly decreased upon PIP2 injection, indicating an impaired functional interaction with PIP2 (PMID: 24947509). This variant has been reported in individuals affected with or suspected of having long QT syndrome, epilepsy, arrhythmia, sudden unexpected death syndrome, or other diseases (PMID: 22629021, 23631430, 28704380, 28606196, 31696929). This variant has been identified in 11/280628 chromosomes (10/19916 East Asian 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

.;D;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

.;M;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.2

D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.77, 0.76

MVP

0.97

MPC

1.4

ClinPred

0.89

GERP RS

4.4

Varity_R

0.85

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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