rs120074184

Positions:

• chr11-2583453-G-A
• chr11-2583453-G-C
• chr11-2583453-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.940G>A​(p.Gly314Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G314A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.36

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 intramembrane_region Pore-forming; Name=Segment H5 (size 20) in uniprot entity KCNQ1_HUMAN there are 54 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 chr11-2583454-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 11-2583453-G-A is Pathogenic according to our data. Variant chr11-2583453-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583453-G-A is described in Lovd as [Pathogenic]. Variant chr11-2583453-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.940G>A	p.Gly314Ser	missense_variant	7/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.940G>A	p.Gly314Ser	missense_variant	7/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.559G>A	p.Gly187Ser	missense_variant	7/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.679G>A	p.Gly227Ser	missense_variant	8/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.496G>A	p.Gly166Ser	missense_variant	3/11			ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Nov 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 03, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -

Long QT syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	May 26, 2018	- -
Pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS2_Moderate, PS3_Moderate, PM1, PM2, PP1_Strong, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9312006, 15051636, 19348785). 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. ClinVar contains an entry for this variant (Variation ID: 3123). This variant is also known as G185S. This missense change has been observed in individuals with long QT syndrome (PMID: 8872472, 9799083, 16922724, 22727609, 22949429). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 314 of the KCNQ1 protein (p.Gly314Ser). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 04, 2024

Not observed at significant frequency 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 a damaging effect as it failed to produce functional homomeric channels, and reduced the K+ current when co-expressed with the wild-type subunit (PMID: 30571187, 9312006); This variant is associated with the following publications: (PMID: 10973849, 25554238, 9799083, 34505893, 34860437, 32048431, 22949429, 9312006, 9693036, 15234419, 15840476, 16038262, 17470695, 19348785, 19716085, 27041150, 27251404, 27041096, 15051636, 9386136, 8872472, 10220144, 12566525, 15028050, 16922724, 19841300, 22581653, 31737537, 32797034, 31493592, 30571187) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2018

The p.G314S pathogenic mutation (also known as c.940G>A), located in coding exon 7 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 940. The glycine at codon 314 is replaced by serine, an amino acid with similar properties. This alteration impacts the highly conserved ion selectivity filter (TIGYGD) located between transmembrane helices S5 and S6. This variant has been identified in multiple patients with long QT syndrome (LQTS) and was reported to co-segregate with disease in several families (Russell MW et al. Hum. Mol. Genet. 1996;5:1319-24; Donger C et al. Circulation. 1997;96:2778-81; Kobori A et al. J. Cardiovasc. Electrophysiol. 2004;15:190-9; Kapa S et al. Circulation. 2009;120:1752-60; Hofman N et al. Neth Heart J. 2011;19:10-16). Functional studies suggest this mutation causes significantly reduced current density in heterologous expression studies (Chouabe C et al. EMBO J. 1997;16:5472-9; Westenskow P et al. Circulation. 2004;109:1834-41). In addition, internal structural analysis indicates that this variant disrupts the ion channel pore and is expected to eliminate the K+ selectivity of the K+ channel (Tao X et al. Science. 2009;326(5960):1668-74; Whorton MR and MacKinnon R. Cell. 2011;147(1):199-208; Ambry internal data). 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:8872472;PMID:9386136;PMID:9693036;PMID:9799083;PMID:10220144;PMID:12566525;PMID:15028050;PMID:15051636;PMID:15840476;PMID:16038262;PMID:16922724;PMID:19348785;PMID:19716085;PMID:19841300;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	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0060	D;.;T
Polyphen		1.0	D;.;D
Vest4		0.94
MutPred		0.97		Gain of sheet (P = 0.0477);.;.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.97
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: rs120074184; hg19: chr11-2604683;