11-2570754-G-A

Position:

chr11-2570754-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.604G>A(p.Asp202Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,610,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D202G) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 9.20

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 Pathogenic. Variant got 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2571325-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 11-2570754-G-A is Pathogenic according to our data. Variant chr11-2570754-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570754-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.604G>A	p.Asp202Asn	missense_variant, splice_region_variant	3/16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.604G>A	p.Asp202Asn	missense_variant, splice_region_variant	3/16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.223G>A	p.Asp75Asn	missense_variant, splice_region_variant	3/16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.343G>A	p.Asp115Asn	missense_variant, splice_region_variant	4/16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.478-12681G>A		intron_variant				ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000806

AC:

AN:

248246

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134702

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1458102

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725574

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:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000202

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	KCNQ1: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 30, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with reduction of the potassium current during the cardiac action potential (Eldstorm et al. 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19862833, 12653681, 25525159, 24372464, 19716085, 28438721, 32048431, 31737537, 31565860, 34426522, 31589614, 32096762, 33990467, 20421371, 34135346, 12051962, 34860437, 34505893, 23392653) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Jun 02, 2022	- -

Long QT syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS4_Strong, PS3_Moderate, PM1, PM2, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This variant causes a G to A nucleotide substitution at the last nucleotide of exon 3 of the KCNQ1 gene and replaces aspartic acid with asparagine at codon 202 of the KCNQ1 protein. Splice site prediction tools suggest that this variant may impact RNA splicing and computational prediction also suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain S3. 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 impairs channel function by accelerating both activation and deactivation kinetics in transfected cells (PMID: 20421371). This variant has been reported in a few individuals affected with or suspected of having long QT syndrome (PMID: 19716085, 31737537, 32893267). This variant has also been observed in homozyous and compound heterozygous sate in two individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 12051962, 24372464), indicating that this variant contributes to disease. This variant has been identified in 3/279614 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 07, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 202 of the KCNQ1 protein (p.Asp202Asn). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 20421371). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 53077). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 12051962, 19716085, 24372464, 31737537). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199472702, gnomAD 0.003%). -

Long QT syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Jun 26, 2023

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 09, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2019

The c.604G>A pathogenic mutation (also known as p.D202N), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 604. This change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the aspartic acid at codon 202 to asparagine, an amino acid with highly similar properties. This alteration has been detected in the heterozygous state in individuals with QT prolongation or borderline QT prolongation, and in the homozygous and compound heterozygous state in individuals with Jervell and Lange-Nielsen syndrome (JLNS) (Wang Z et al. Mol Genet Metab. 2002;75:308-16; Al-Aama JY. Clin Genet. 2015;87(1):74-9). In one study, this alteration was reported to result in altered splicing; however, supporting evidence was not provided (Kapplinger J et al. Heart Rhythm. [Abstract #AB22-05] 2016 May;13(5):S1-S608). In functional in vitro analyses, this alteration demonstrated adverse affects on the current amplitude and cardiac action potential of the voltage-gated potassium ion channel (Eldstrom J et al. J Gen Physiol. 2010;135:433-48). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 18, 2023

This variant causes a G to A nucleotide substitution at the last nucleotide of exon 3 of the KCNQ1 gene and replaces aspartic acid with asparagine at codon 202 of the KCNQ1 protein. Splice site prediction tools suggest that this variant may impact RNA splicing and computational prediction also suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain S3. 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 impairs channel function by accelerating both activation and deactivation kinetics in transfected cells (PMID: 20421371). This variant has been reported in a few individuals affected with or suspected of having long QT syndrome (PMID: 19716085, 31737537, 32893267). This variant has also been observed in homozyous and compound heterozygous sate in two individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 12051962, 24372464), indicating that this variant contributes to disease. This variant has been identified in 3/279614 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jervell and Lange-Nielsen syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 12, 2023

Variant summary: KCNQ1 c.604G>A (p.Asp202Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 248246 control chromosomes (gnomAD). c.604G>A has been reported in the literature in the heterozygous state in individuals with QT prolongation or borderline QT prolongation, and in the homozygous and compound heterozygous state in individuals with Jervell and Lange-Nielsen syndrome (JLNS) (examples: Wang_2002, Al-Aama_2014, Akgun-Dogan_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that this variant impairs normal function of the protein (Eldstrom_2009). The following publications have been ascertained in the context of this evaluation (PMID: 34860437, 24372464, 20421371, 12051962, 27920829). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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:12051962;PMID:12653681;PMID:19716085;PMID:20421371). 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

.;D;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

.;H;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.99, 0.99

MutPred

0.97

.;Gain of MoRF binding (P = 0.0343);.;

MVP

0.99

MPC

1.2

ClinPred

1.0

GERP RS

4.4

Varity_R

0.91

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.16

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