rs17215479

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_000218.3(KCNQ1):c.643G>A(p.Val215Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,932 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1O:1

Conservation

PhyloP100: 7.61

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 Uncertain_significance. Variant got 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

PP5

Variant 11-2571363-G-A is Pathogenic according to our data. Variant chr11-2571363-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53081.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, not_provided=1, Likely_pathogenic=4}. Variant chr11-2571363-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.643G>A	p.Val215Met	missense_variant	4/16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 link	c.643G>A	p.Val215Met	missense_variant	4/16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.262G>A	p.Val88Met	missense_variant	4/16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.382G>A	p.Val128Met	missense_variant	5/16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.478-12072G>A		intron_variant				ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250306

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1460824

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726760

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

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

Alfa

AF:

0.000143

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2025	In vitro functional studies demonstrated that V215M alters potassium current kinetics; however, a complete loss of function was not demonstrated and it is uncertain whether these experiments replicate in vivo conditions (PMID: 20421371, 27690226); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26633542, 19841300, 23098067, 22949429, 25916402, 27690226, 37937776, 34426522, 19716085, 31865382, 34505893, 37449562, 32893267, 1484536, 23392653, 20421371, 16414944, 28438721, 19632626, 28589536) -

Long QT syndrome 1

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Short QT syndrome is associated with gain of function variants, while long QT syndrome (LQTS), atrial fibrillation and Jervell and Lange-Nielson syndrome (JLNS) are associated with loss of function variants (OMIM, PMID: 19632626, PMID: 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is a more severe form of LQTS, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - Variants in this gene are known to have reduced penetrance (GeneReviews, OMIM). These variants are likely to cause long QT syndrome or atrial fibrillation. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2), p.(Val215Gly) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Minor amino acid change, moderate conservation. (I) 0600 - Variant is located in the annotated transmembane S3 domain (Invitae Protein Topology). (I) 0710 - Another variant affecting the same amino acid and comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Val215Gly): ClinVar, VUS x2. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. ClinVar: VUS x1. PMID: 16414944: one family with LQTS. PMID: 19841300: one patient with LQTS. PMID: 23098067: one LQTS patient. PMID: 23392653: one patient with autosomal recessive LQTS and no deafness, in trans with another KCNQ1 variant, W3292X. PMID: 28589536: considered a VUS. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has limited functional evidence supporting abnormal protein function. PMID: 20421371: Patch clamp experiments on mammalian cells (mouse) demonstrated a positive shift in activation, slowed channel activation, and accelerated deactivation, when co-expressed with KCNE1. PMID: 27690226: clamp tests in Xenopus laevis oocytes demonstrated that this variant altered the channel function. Patch clamp assays have been shown to be unreliable therefore, results from these studies are used with caution during variant classification. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign -
Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000218.3:c.643G>A (chr11:2571363) in KCNQ1 was detected in 206 heterozygotes out of 58K WGS Icelanders (MAF= 0,178%). Following imputation in a set of 166K Icelanders (572 imputed heterozyogtes) we observed an association with an elongation of the qt interval on ECG using measurements from 80068 individuals (Effect (SD)= 0.83, P= 9.16e-31). This variant has been reported in ClinVar previously as uncertain significance. Based on ACMG criteria (PS4, PP2, PP3, PP5) this variant classifies as likely pathogenic. -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the KCNQ1 protein (p.Val215Met). This variant is present in population databases (rs17215479, gnomAD 0.007%). This missense change has been observed in individuals with KCNQ1-related conditions (PMID: 16414944, 22949429, 23098067, 23392653; external communication). ClinVar contains an entry for this variant (Variation ID: 53081). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 20421371). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2024

The p.V215M variant (also known as c.643G>A), located in coding exon 4 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 643. The valine at codon 215 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals with features of long QT syndrome (LQTS) or who were suspected to have LQTS, and co-occurred in trans with a nonsense variant in KCNQ1 in a proband with severe QTc prolongation and normal hearing (Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Pundi KN et al. Heart Rhythm, 2015 Apr;12:776-81). This variant has been reported as an Icelandic founder mutation associated with QTc prolongation; however, this variant was associated with a less severe clinical phenotype and lower rate of sudden cardiac arrest/death when compared to other pathogenic KCNQ1 variants (Sveinbjornsson G. et al. J Am Heart Assoc. 2023 Jul;12(14):e029845). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 26, 2023

This missense variant replaces valine with methionine at codon 215 of the KCNQ1 protein. 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). Functional studies have shown that this variant causes a rightward shift in the voltage dependence of channel activation and changes channel activation and deactivation kinetics (PMID: 20421371, 27690226, 31865382). This variant has been reported in several heterozygous individuals affected with or suspected of having long QT syndrome (PMID: 16414944, 19716085, 19841300, 23098067, 32893267, ClinVar SCV001484536.3). The variant has also been observed in compound heterozygous state with a known pathogenic KCNQ1 variant in an individual with severe long QT syndrome in the absence of an auditory phenotype, whose father was an asymptomatic carrier with prolonged QTc interval (PMID: 23392653). This variant has been described as a founder mutation in the Icelandic population and has shown a significant association with prolonged QTc interval in a large population study (PMID: 37449562). However, compared to other pathogenic variants that cause long QT syndrome, this variant is not associated with severe clinical events such as sudden cardiac death. This variant has only been identified in 3/250306 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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:16414944;PMID:19716085;PMID:19841300;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

Benign

0.21

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

.;D;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.5

.;L;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.9

N;N;N

REVEL

Pathogenic

0.81

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.99

.;D;.

Vest4

0.78, 0.77

MutPred

0.87

.;Gain of helix (P = 0.062);.;

MVP

0.97

MPC

1.2

ClinPred

0.87

GERP RS

4.3

Varity_R

0.35

gMVP

0.88

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