rs120074184

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 9.36

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 18 ACMG points.

PM1

In a short_sequence_motif Selectivity filter (size 5) in uniprot entity KCNQ1_HUMAN there are 24 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 rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.940G>A	p.Gly314Ser	missense_variant	Exon 7 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 link	c.940G>A	p.Gly314Ser	missense_variant	Exon 7 of 16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.559G>A	p.Gly187Ser	missense_variant	Exon 7 of 16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.679G>A	p.Gly227Ser	missense_variant	Exon 8 of 16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.496G>A	p.Gly166Ser	missense_variant	Exon 3 of 11			ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:5

Sep 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in Short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause Long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated pore domain (UniProt). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. The p.(Gly314Asp) variant has been identified in three LQTS patients (PMIDs:15840476,19841300). The p.(Gly314Cys) and p.(Gly314Arg) variants have both been identified in one LQTS patient each (PMIDs: 19716085, 15840476). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least 15 LQTS patients (PMIDs: 19716085, 22659597, 22727609, 15840476, ClinVar, VCGS). (SP) 1002 - Moderate functional evidence supporting abnormal protein function. Patch clamp analysis indicates that this variant reduces channel current in a dominant negative manner (PMID: 19348785). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 20, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2023

Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2024

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Pathogenic:3

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PS2_Moderate, PS3_Moderate, PM1, PM2, PP1_Strong, PP3 -

May 26, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 8872472, 9799083, 16922724, 22727609, 22949429). This variant is also known as G185S. ClinVar contains an entry for this variant (Variation ID: 3123). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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, 15051636, 19348785). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Mar 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNQ1 c.940G>A; p.Gly314Ser variant (rs120074184, ClinVar Variation ID: 189773), is reported in the literature in multiple individuals affected with Long QT syndrome (Akgun-Dogan 2022, Giudicessi 2012). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional analyses of the variant protein show significantly reduced current density (Chouabe 1997, Westenskow 2004). Computational analyses predict that this variant is deleterious (REVEL: 0.969). Based on available information, this variant is considered to be pathogenic. REFERENCES Akgun-Dogan O et al. Mutational spectrum of congenital long QT syndrome in Turkey; identification of 12 novel mutations across KCNQ1, KCNH2, SCN5A, KCNJ2, CACNA1C, and CALM1. J Cardiovasc Electrophysiol. 2022 Feb;33(2):262-273. PMID: 34860437. Chouabe C et al. Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. EMBO J. 1997 Sep 1;16(17):5472-9. PMID: 9312006. Giudicessi JR et al. Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. PMID: 22949429. Westenskow P et al. Compound mutations: a common cause of severe long-QT syndrome. Circulation. 2004 Apr 20;109(15):1834-41. PMID: 15051636. -

Cardiovascular phenotype

Pathogenic:1

Jun 08, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.8

H;.;.

PrimateAI

Pathogenic

0.81

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

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

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