rs120074194

Positions:

• chr11-2572871-G-A
• chr11-2572871-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.806G>A​(p.Gly269Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. G269R) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 9.42

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2572870-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 11-2572871-G-A is Pathogenic according to our data. Variant chr11-2572871-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572871-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.806G>A	p.Gly269Asp	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	c.806G>A	p.Gly269Asp	missense_variant	6/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.425G>A	p.Gly142Asp	missense_variant	6/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.545G>A	p.Gly182Asp	missense_variant	7/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-10564G>A		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74388

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 14, 2017	The p.Gly269Asp variant (rs120074194) has been reported to segregate with disease in two unrelated families (Donger 1997 and Wang 2002), and was also identified in an individual with a history of near-drowning and a high clinical probability of having long QT syndrome (Choi 2004). The p.Gly269Asp variant was also identified in four out of 2,500 patients (0.16%) suspected of having long-QT syndrome (Kapplinger 2009), but is absent from general population databases such as 1000 Genomes, the Exome Variant Server (ESV), and the Genome Aggregation Database (gnomAD) browser. Functional studies demonstrate that the KCNQ1 p.Gly269Asp substitution eliminates activity of potassium channels (Chen 2003 and Chouabe 1997). Furthermore, another variant at this position (p.Gly269Ser) has been identified in individuals with long QT syndrome (Ackerman 1999, Choi 2004, Kapplinger 2009, Shimizu 2004, and Wu 2014). Based on the available evidence, the p.Gly269Asp variant is considered pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2022	Reported in multiple individuals in association with LQTS (Donger et al., 1997; Splawski et al., 2000; Moss et al., 2007; Kapplinger et al., 2009); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate this variant results in a loss of function of the ion channel (Chouabe et al., 1997; Chen et al., 2003); This variant is associated with the following publications: (PMID: 23130128, 21185501, 19815527, 27761162, 10973849, 14678125, 15466642, 17470695, 12205113, 22629021, 23139254, 25649125, 9312006, 19716085, 15840476, 22581653, 31980526, 34319147, 12051962, 12522251, 9386136) -

Congenital long QT syndrome Pathogenic:1 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:9386136;PMID:10973849;PMID:12051962;PMID:14678125;PMID:15466642;PMID:15840476;PMID:19716085;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2023	The p.Gly269Asp variant in KCNQ1 has been reported in the heterozygous state in at least 36 individuals with long QT syndrome (LQTS) and in the compound heterozygous state in 1 individual with Jervell and Lange-Nielsen syndrome (JNLS). This variant segregated with LQTS in 7 relatives from 2 families (Donger 1997 PMID: 9386136, Wang 2002 PMID: 12051962, Moss 2007 PMID: 17470695). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID 3145) and was identified in 0.002% (1/41470) African/African American and in 0.001% (1/68042) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant results in a non-functional potassium channel (Chouabe 1997 PMID: 9312006, Chen 2003 PMID: 12522251) and computational prediction tools and conservation analyses suggest that this variant impacts the protein. At least 1 additional variant involving this codon (p.Gly269Ser) has been identified in individuals with LQTS and is classified as pathogenic by several clinical laboratories in ClinVar (Variation ID: 3144). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM5, PP3, PS3_Supporting, PM2_supporting. -

Long QT syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 04, 1997

- -

KCNQ1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2024

The KCNQ1 c.806G>A variant is predicted to result in the amino acid substitution p.Gly269Asp. This variant is also known as p.Gly142Asp in the literature. This variant was reported in numerous individuals with long QT syndrome and sudden cardiac death (Donger et al. 1997. PubMed ID: 9386136; online appendix, Goldenberg et al. 2011. PubMed ID: 21185501; eTable 3, Guo et al. 2021. PubMed ID: 34076677; Table SXIII, Choi et al. 2021. PubMed ID: 34319147; Table S1, Schwartz et al. 2021. PubMed ID: 34505893). Functional studies showed that this variant results in a loss-of-function potassium channel (Chouabe et al. 1997. PubMed ID: 9312006; Chen et al. 2003. PubMed ID: 12522251). This variant has not been reported in a large population database, indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.Gly269Ser, p.Gly269Arg) have been reported to be causative for long QT syndrome (Human Gene Mutation Database). Taken together, the c.806G>A (p.Gly269Asp) variant is interpreted as pathogenic. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2023

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 269 of the KCNQ1 protein (p.Gly269Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 9386136, 10973849, 12051962, 17470695). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3145). 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: 9312006, 12522251). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2022

The p.G269D pathogenic mutation (also known as c.806G>A), located in coding exon 6 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 806. The glycine at codon 269 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in a number of individuals with long QT syndrome (LQTS) and was shown to segregate with the disease in a few families (Donger C et al. Circulation. 1997;96:2778-81; Splawski I et al. Circulation. 2000;102:1178-85; Wang Z et al. Mol. Genet. Metab. 2002;75:308-16; Moss AJ et al. Circulation. 2007;115:2481-9; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303). In vitro studies suggested that this alteration would affect channel activity (Chouabe C et al. EMBO J. 1997;16:5472-9; Chen YH et al. Science. 2003;299:251-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, another alteration at the same amino acid position, G269S, has also been reported in association with LQTS and to segregate with the disease (Shimizu W et al. J. Am. Coll. Cardiol. 2004;44:117-25; Chen S et al. Clin. Genet. 2003;63:273-82; Berge KE et al. Scand. J. Clin. Lab. Invest. 2008;68:362-8). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.9	D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.95, 0.94
MutPred		0.90		.;Loss of stability (P = 0.077);.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.99
gMVP		0.99

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

Other links and lift over

dbSNP: rs120074194; hg19: chr11-2594101;