rs120074193

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.805G>A(p.Gly269Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,810 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G269D) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 9.42

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 16 ACMG points.

PM1

In a helix (size 25) in uniprot entity KCNQ1_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) in NM_000218.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2572871-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 11-2572870-G-A is Pathogenic according to our data. Variant chr11-2572870-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572870-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.805G>A	p.Gly269Ser	missense_variant	6/16	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.805G>A	p.Gly269Ser	missense_variant	6/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.424G>A	p.Gly142Ser	missense_variant	6/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.544G>A	p.Gly182Ser	missense_variant	7/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.478-10565G>A		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250528

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135720

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461454

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 22, 2019

The c.805G>A; p.Gly269Ser variant (rs120074193, ClinVarID 3144 ) was first reported in a 16-year-old asymptomatic boy, whose cousin passed out in a swimming pool due to a triggered cardiac event (Ackerman 1999). This patient's QT was measured at 470 ms. Since then, the p.Gly269Ser variant has been reported in patients with long QT syndrome, including at least four families, where the variant segregated with disease (Wu 2014, Fujii 2017). Additionally, other amino acid substitutions at this codon (p.Gly269Asp, p.Gly269Val) have been reported in individuals with LQTS and are considered pathogenic (Donger 1997, and ClinVar IDs: 3145 & 200899). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 269 is highly conserved in the transmembrane S5 domain, and functional studies demonstrate that the p.Gly269Ser variant causes a reduction in potassium ion current and protein stability (Wu 2014 and Verma 2010). Computational analyses by SIFT and PolyPhen-2 also predict that this variant is deleterious. Overall, this variant is considered to be pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant may cause abnormal assembly and stability of the potassium channel and exert moderate dominant-negative suppression of the potassium channel (Verma et al., 2009; Wu et al., 2014; Wang et al., 2014); 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: 25348405, 20044973, 19808498, 27816319, 22677073, 29740400, 29439887, 15234419, 15176425, 18752142, 19841300, 9312006, 9386136, 10973849, 12051962, 12522251, 17470695, 31328865, 29151524, 25082577, 33087929, 10560595, 34319147, 32470535, 34505893, 24184248) -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 269 of the KCNQ1 protein (p.Gly269Ser). This variant is present in population databases (rs120074193, gnomAD 0.003%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 15176425, 15234419, 18752142, 24184248). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3144). 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: 20044973, 24184248). This variant disrupts the p.Gly269 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9312006, 9386136, 10973849, 12051962, 12522251, 17470695). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2019

The p.G269S pathogenic mutation (also known as c.805G>A), located in coding exon 6 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 805. The glycine at codon 269 is replaced by serine, an amino acid with similar properties. This mutation has been detected in numerous individuals with long QT syndrome (LQTS), some demonstrating symptoms triggered by physical exertion such as swimming; segregation was reported in affected family members from several families (Ackerman MJ et al. Mayo Clin. Proc., 1999 Nov;74:1088-94; Chen S et al. Clin. Genet., 2003 Apr;63:273-82; Shimizu W et al. J. Am. Coll. Cardiol., 2004 Jul;44:117-25; Berge KE et al. Scand. J. Clin. Lab. Invest., 2008;68:362-8). In addition, multiple functional studies suggest this alteration leads to deficient protein function (Murray A et al. J. Med. Genet., 2002 Sep;39:681-5; Wu J et al. J. Am. Coll. Cardiol., 2014 Mar;63:819-27). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:10560595;PMID:12205113;PMID:12702160;PMID:14678125;PMID:15466642;PMID:15840476;PMID:17905336;PMID:18752142;PMID:19716085;PMID:19808498;PMID:20044973;PMID:15234419;PMID:17470695). 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

0.93

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

.;L;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Pathogenic

0.93

Sift

Benign

0.070

T;D;D

Sift4G

Benign

0.075

T;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.96, 0.94

MutPred

0.89

.;Loss of stability (P = 0.0637);.;

MVP

0.98

MPC

1.2

ClinPred

0.99

GERP RS

3.7

Varity_R

0.97

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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