11-2847803-G-A

Position:

chr11-2847803-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM5BP4

The NM_000218.3(KCNQ1):c.1831G>A(p.Asp611Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000757 in 1,571,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. D611Y) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:11B:1O:1

Conservation

PhyloP100: 4.89

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:

KCNQ1-AS1 (HGNC:):

KCNQ1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a region_of_interest Interaction with AKAP9 (size 28) in uniprot entity KCNQ1_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_000218.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2847803-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.38976586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1831G>A	p.Asp611Asn	missense_variant	16/16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1831G>A	p.Asp611Asn	missense_variant	16/16	1	NM_000218.3	ENSP00000155840.2		P51787-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

181208

Hom.:

AF XY:

0.0000617

AC XY:

AN XY:

97278

show subpopulations

Gnomad AFR exome

AF:

0.0000917

Gnomad AMR exome

AF:

0.000108

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000725

Gnomad SAS exome

AF:

0.0000820

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000812

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000761

AC:

108

AN:

1419094

Hom.:

Cov.:

AF XY:

0.0000755

AC XY:

AN XY:

702052

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.000154

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000534

Gnomad4 SAS exome

AF:

0.0000866

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000807

Gnomad4 OTH exome

AF:

0.0000681

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000641

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000117

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 13, 2024	This missense variant replaces aspartic acid with asparagine at codon 611 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 22727609, 33614747), in an individual referred for long QT syndrome test (PMID: 19716085), and in an individual suspected of having Jervell and Lange-Nielsen Syndrome (27917693). It has also been reported in an individual among exome sequencing participants not selected for cardiovascular disorders (PMID: 23861362) and in another two individuals with normal QTc internal (PMID: 26159999, 27917693). This variant has been identified in 17/212554 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, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PM2, PM5 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 611 of the KCNQ1 protein (p.Asp611Asn). This variant is present in population databases (rs147445322, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Jervell and Lang-Nielsen syndrome and/or clinical features of long QT syndrome (PMID: 19716085, 22727609, 25554238, 27917693, 30530868). ClinVar contains an entry for this variant (Variation ID: 67059). 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) has been performed at Invitae 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. 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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 10, 2018	The p.Asp611Asn variant in KCNQ1 has been reported in 3 individuals with Long QT syndrome (Andrsova 2012, Hedley 2009, Kapplinger 2009). It was also identified in 1 child with congenital profound hearing loss and a borderline QTc of 446 ms ec who had a second VUS in KCNQ1 in trans. The variant was found in the heterozy gous state in the child's unaffected mother (Wang 2017). In another study this variant was found in a heterozygous individual whose mean QTc interval was not s tatistically different than the mean QTc interval observed in 6061 Danish contro l individuals that were negative for the variant (Ghouse 2015). This variant ha s been identified in several populations by the Genome Aggregation Database with the highest allele frequency of 10/86082 European chromosomes (gnomAD, http://g nomad.broadinstitute.org/; dbSNP rs147445322) and is reported in ClinVar (Variat ion ID: 67059) by several laboratories or studies. Although the variant has been seen in unaffected individuals and in the general population, we cannot rule ou t a causative role due to reduced penetrance and variable expressivity that has been noted in some long QT families. Computational prediction tools and conserva tion analysis do not provide strong support for or against an impact to the prot ein. In summary, due its presence in both affected and unaffected individuals, l imited familial segregation data, and its frequency in the general population, t he clinical significance of the p.Asp611Asn variant is uncertain. ACMG/AMP Crite ria applied: None. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	Variant summary: KCNQ1 c.1831G>A (p.Asp611Asn) results in a conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal (IPR013821) of 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 7.2e-05 in 181208 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in KCNQ1 causing Long QT Syndrome (7.2e-05 vs 0.0001), allowing no conclusion about variant significance. c.1831G>A has been reported in the literature in individuals affected with Long QT Syndrome or related phenotypes (Kapplinger_2009, Thauvin-Robinet_2019, Andrsova_2012, Tse_2021, Kwok_2018, Illikova_2015), although one publication found no significant difference in electrocardiogram results between a carrier and non-carriers of the variant (Ghouse_2015). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 26159999, 27917693, 31019283, 22727609, 33614747, 30530868, 25554238). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2024	Reported multiple times in association with LQTS or sudden cardiac arrest, though many publications lack patient-specific data (PMID: 19716085, 22727609, 25554238, 28749187, 30530868, 29884292); Reported in a Danish cohort screened for LQTS variants where QTc intervals in carriers were not statistically different compared with non-carriers (PMID: 26159999); Reported in a 6-year-old Chinese proband with congential profound deafness and QTc of 446. He also harbored a second missense variant in trans in the KCNQ1 gene. The p.(D611N) variant was inherited from his mother with normal hearing and a normal QTc interval (PMID: 27917693); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 22727609, 23861362, 28749187, 22378279, 19862833, 25554238, 29197658, 26633542, 25854863, 30530868, 29884292, 31019283, 32048431, 33614747, 19716085, 26159999, 27917693) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 20, 2023	- -

Long QT syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Nov 21, 2018

- -

KCNQ1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2024

The KCNQ1 c.1831G>A variant is predicted to result in the amino acid substitution p.Asp611Asn. This variant has been reported in individuals with long QT syndrome (Kapplinger et al. 2009. PubMed ID: 19716085; Hedley et al. 2009. PubMed ID: 19862833). Additionally, this variant has been reported compound heterozygous in a patient with severe hearing loss (Wang et al. 2016. PubMed ID: 27917693). One publication found no difference in QT intervals, syncopy, or morbidity in carriers versus non-carriers (Ghouse et al. 2015. PubMed ID: 26159999). This variant is reported in 0.010% of alleles in individuals of African, European (non-Finnish) and Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2022

The c.1831G>A (p.D611N) alteration is located in exon 16 (coding exon 16) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 1831, causing the aspartic acid (D) at amino acid position 611 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 01, 2023

This missense variant replaces aspartic acid with asparagine at codon 611 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 22727609, 33614747), in an individual suspected to be affected with long QT syndrome (PMID: 19716085), and in an individual suspected of having Jervell and Lange-Nielsen Syndrome (27917693). It has also been reported in individuals without diagnoses of KCNQ1-related disorders (PMID: 23861362, 26159999, 27917693). This variant has been identified in 17/212554 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

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:19716085;PMID:19862833;PMID:22378279). 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

0.093

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.;.

Eigen

Benign

-0.0074

Eigen_PC

Benign

0.0049

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

T;T;T

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.99

L;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.53

N;N;.

REVEL

Uncertain

0.59

Sift

Benign

0.19

T;T;.

Sift4G

Benign

0.23

T;T;.

Polyphen

0.94

P;.;.

Vest4

0.76

MVP

0.95

MPC

0.38

ClinPred

0.034

GERP RS

2.9

Varity_R

0.52

gMVP

0.82

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