rs199472813

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5

The NM_000218.3(KCNQ1):c.1768G>A(p.Ala590Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,536 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. A590P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2O:1

Conservation

PhyloP100: 2.53

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.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000218.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

PP5

Variant 11-2778011-G-A is Pathogenic according to our data. Variant chr11-2778011-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53015.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=1, not_provided=1, Uncertain_significance=1}. Variant chr11-2778011-G-A is described in Lovd as [Pathogenic]. Variant chr11-2778011-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1768G>A	p.Ala590Thr	missense_variant	15/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1768G>A	p.Ala590Thr	missense_variant	15/16	1	NM_000218.3	P1	P51787-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250944

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135728

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:

0.0000467

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461384

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000378

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000574

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 15, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jan 13, 2022	- -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2022	Reported in association with sinus bradycardia and LQTS or suspected LQTS (Lupoglazoff et al., 2004; Tester et al., 2005; Kapa et al., 2009; Ebrahim et al., 2017; Smith et al., 2017; Strand et al., 2020); of note, one of the probands with a prolonged QTc was homozygous for this variant and had normal hearing (Smith et al., 2017); 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: 19841300, 34505893, 31565860, 32421437, 17329209, 15840476, 22949429, 17329207, 18174212, 19825999, 19322600, 16623272, 28491806, 28532774, 24713462, 32048431, 31589614, 14998624) -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 590 of the KCNQ1 protein (p.Ala590Thr). This variant is present in population databases (rs199472813, gnomAD 0.004%). This missense change has been observed in individuals with definite or suspected long QT syndrome (PMID: 14998624, 22949429, 23130128, 24713462, 28491806). ClinVar contains an entry for this variant (Variation ID: 53015). 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: 24713462). For these reasons, this variant has been classified as Pathogenic. -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 14, 2023

This missense variant replaces alanine with threonine at codon 590 of the KCNQ1 protein. This variant is found within a highly conserved region (a.a.585-607) of C-terminal cytoplasmic coiled-coil domain. Rare nontruncating 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 may adversely affect channel trafficking to the cell surface and function (PMID: 24713462). This variant has been reported in about ten unrelated individuals affected with long QT syndrome which was congenital in half of the probands (PMID: 14998624, 15840476, 16623272, 19841300, 23130128, 24713462, 28491806, 28532774, 32421437, 34395343). The variant has been observed in homozygous state in one of these individuals, who was from a consanguineous family and showed severe phenotypes but no hearing loss (PMID: 28491806). Both parents and two siblings were unaffected heterozygous and a distant cousin had sudden death at young age also in the setting of consanguinity. This variant has been identified in 3/282306 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Nov 13, 2013

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Ala590Thr Based on the data reviewed below we consider it a variant of uncertain significance, likely disease causing. The variant has been seen in one case of long QT, another case of possible neonatal long QT, and one case of drug-induced long QT. There is no segregation data available. Lupoglazoff et al (2004) first reported this variant in their French cohort. They observed it in a neonate with long QT syndrome. The patient was a male who presented with neonatal bradycardia and a QTc of 460 ms. At follow-up at 6 years of age he was asymptomatic. They note that the variant was inherited from the mother but no phenotypic data on the mother is provided. I had our peds EP team review this case and they felt the data reported was perhaps suspicious for a diagnosis of long QT but did not strongly support it. Couderc et al (2012) included a patient with this variant in an analysis of QT-RR relationship in patients with long QT, however the data for that study was pulled from a French database so this may be the same case that was reported by Lupoglazoff et all (2004). The variant was also reported in a compendium of variants found in Dr. Ackerman's research lab (Tester et al 2005). The variant was observed in 1 of 541 individuals with "suspected" long QT syndrome enrolled in Dr. Ackerman's studies. Individual phenotypic data was not reported, however sufficient data was available to calculate a Schwartz score in 77% of cases. A Schwartz score ? 4 (indicating high confidence in the diagnosis) was present 29% of the overall cohort and 40% of individuals with a KCNQ1 variant. The overall yield was 50%, compared to 70% in studies where all the patients had a firmer diagnosis of long QT syndrome. Taken together these data suggest that a proportion of patients in this study did not in fact have long QT syndrome. However, the same group later included a case with this variant in two other publications and noted that only cases with a strong diagnosis (Schwartz score ? 4 or QTc ? 480 ms were included) (Kapa et al 2009, Giudicessi et al 2012). Given ascertainment methods for the three papers it is likely they are all referring to the same case. I suspect this case was also included in a paper by Goldenberg et al (2011) and one by Barsheshet et al (2012) as Dr. Ackerman is a co-author on both and cases from his cohort were included. Goldenberg et al (2011) list three individuals with p.Ala590Thr, however the study included people with long QT and genotype-positive, phenotype-negative relatives, and it is unclear whether those three individuals had phenotype. Novotny et al (2006) reported the variant in a study on drug-induced long QT, though unfortunately the paper is in Czech. Using google translate it looks like they observed the variant in male with a QTc of 450 ms while on venlafixine (Effexor). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The alanine at codon 590 is conserved across mammals but is a serine in fugu and c elegans. Other variants have been reported in association with disease at nearby codons (p.Thr587Met, p.Gly589Asp, p.Arg591Cys, p.Arg591His, p.Arg594Gln, p.Arg594Pro, p.Glu596Lys). In total the variant has not been seen in ~8100 published controls and individuals from publicly available population datasets. There is no variation at codon 590 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6500 Caucasian and African American individuals (as of February 27th, 2013). The variant is in 1000 genomes and dbSNP (rs199472813) but only in reference to the reports with long QT syndrome.The variant was not observed in the followin -

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:14998624;PMID:15840476;PMID:16623272;PMID:17329209;PMID:19841300;PMID:17329207). 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

0.31

CardioboostArm

Uncertain

0.86

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

M;.;.;.

MutationTaster

Benign

0.95

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;.;N;.

REVEL

Pathogenic

0.82

Sift

Benign

0.14

T;.;T;.

Sift4G

Benign

0.17

T;.;T;.

Polyphen

0.89

P;.;P;.

Vest4

0.88

MutPred

0.74

Gain of helix (P = 0.062);.;.;.;

MVP

0.96

MPC

1.0

ClinPred

0.83

GERP RS

3.1

Varity_R

0.18

gMVP

0.95

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