11-2777991-G-A

Position:

chr11-2777991-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM5PP3_ModeratePP5

The NM_000218.3(KCNQ1):c.1748G>A(p.Arg583His) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,613,672 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. R583C) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4O:1

Conservation

PhyloP100: 3.92

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 5 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2777990-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

PP5

Variant 11-2777991-G-A is Pathogenic according to our data. Variant chr11-2777991-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67053.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, not_provided=1, Uncertain_significance=5}. Variant chr11-2777991-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1748G>A	p.Arg583His	missense_variant	15/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1748G>A	p.Arg583His	missense_variant	15/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152174

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251018

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461498

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74330

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:

0.0000942

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Oct 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	May 06, 2024	- -

Cardiac arrhythmia

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 14, 2023	This missense variant replaces arginine with histidine at codon 583 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 does not cause severe functional impairment in transfected cells (PMID: 28749435). This variant has been reported in at least 4 unrelated individuals affected with long QT syndrome (15851171, 16414944, 18822425, 22456477, 24363352, 2460699, 26318259, 28749435, 32893267), in an individual affected with sudden unexpected death and epilepsy (PMID: 26423924), and in an individual suspected of having epilepsy (PMID: 31696929). This variant has been identified in 5/282380 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2024	Variant summary: KCNQ1 c.1748G>A (p.Arg583His) results in a non-conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal domain (IPR013821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251018 control chromosomes. c.1748G>A has been reported in the literature in multiple individuals affected with Arrhythmia and in two families, this variant has been shown to segregate with disease (Kanters_2004, Li_2024). These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function. While one experiment study shows that the variant results in impeded channel protein activation in the whole-cell patch-clamp assay and >70% reduction of forskolin-induced channel current (Li_2024), the other failed to find a signicifant effect of this variant on channel activity (Zullo_2017). The following publications have been ascertained in the context of this evaluation (PMID: 15851171, 38657442, 16414944, 34505893, 28749435). ClinVar contains an entry for this variant (Variation ID: 67053). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces arginine with histidine at codon 583 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 does not cause severe functional impairment in transfected cells (PMID: 28749435). This variant has been reported in at least 4 unrelated individuals affected with long QT syndrome (15851171, 16414944, 18822425, 22456477, 24363352, 2460699, 26318259, 28749435, 32893267), in an individual affected with sudden unexpected death and epilepsy (PMID: 26423924), and in an individual suspected of having epilepsy (PMID: 31696929). This variant has been identified in 5/282380 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 09, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 583 of the KCNQ1 protein (p.Arg583His). This variant is present in population databases (rs199473482, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 15851171, 16414944, 24363352, 28749435). ClinVar contains an entry for this variant (Variation ID: 67053). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 28749435). 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 provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15851171, 16414944, 28749435, 34505893, 22581653, 29021305, 24606995) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2023

The p.R583H variant (also known as c.1748G>A), located in coding exon 15 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1748. The arginine at codon 583 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in an individual with arrhythmia, a sudden unexplained death in epilepsy cohort, and long QT syndrome cohorts; however, in some cases, clinical detail was limited and additional variants in other arrhythmia-related genes were also detected. In addition, some reported cases may overlap (Kanters JK et al. Heart Rhythm, 2004 Sep;1:285-92; Christiansen M et al. BMC Med Genet, 2014 Mar;15:31; Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Barsheshet A et al. Circulation, 2012 Apr;125:1988-96; Yoshinaga M et al. Circ Arrhythm Electrophysiol, 2014 Feb;7:107-12; Coll M et al. Int J Legal Med, 2016 Mar;130:331-9; Zullo A et al. Int J Mol Sci, 2017 Jul;18; Schwartz PJ et al. Eur Heart J, 2021 Dec;42:4743-4755). One functional study indicated this variant may impact some channel electrophysiological parameters, but not significantly impact current density; however, additional evidence is needed to confirm these findings (Zullo A et al. Int J Mol Sci, 2017 Jul;18). This amino acid position is well 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. -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15851171;PMID:16414944). 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

0.27

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.060

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

M;.;.;.

MutationTaster

Benign

0.60

N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

N;.;N;.

REVEL

Pathogenic

0.78

Sift

Benign

0.031

D;.;D;.

Sift4G

Uncertain

0.052

T;.;D;.

Polyphen

0.27

B;.;D;.

Vest4

0.57

MutPred

0.67

Loss of MoRF binding (P = 0.0125);.;.;.;

MVP

0.96

MPC

1.3

ClinPred

0.84

GERP RS

3.1

Varity_R

0.073

gMVP

0.86

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

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