rs151344631

chr11-2571333-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_Very_Strong

The NM_000218.3(KCNQ1):c.613G>A(p.Val205Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,162 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V205V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 7.36

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 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000218.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 11-2571333-G-A is Pathogenic according to our data. Variant chr11-2571333-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2571333-G-A is described in Lovd as [Pathogenic]. Variant chr11-2571333-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.613G>A	p.Val205Met	missense_variant	4/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.613G>A	p.Val205Met	missense_variant	4/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.232G>A	p.Val78Met	missense_variant	4/16	1
KCNQ1	ENST00000496887.7	c.352G>A	p.Val118Met	missense_variant	5/16	5
KCNQ1	ENST00000646564.2	c.478-12102G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250528 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135708

Gnomad AFR exome AF: 0.0000618

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461010 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726838

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74312

Gnomad4 AFR AF: 0.000121

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Sep 04, 2023	The KCNQ1 c.613G>A (p.Val205Met) variant has been reported in the medical literature in individuals affected with long QT syndrome (Arbour L et al., PMID: 18580685; Eldstrom J et al., PMID: 25444851; Jackson H et al., PMID: 23844633; Natarajan P et al., PMID: 27831900). This variant is only observed on 3/281,894 total alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KCNQ1 protein function. Functional studies suggest that this variant reduces KCNQ1 channel activity, indicating impact to protein function (Arbour L et al., PMID: 18580685; Eldstrom J et al., PMID: 25444851). This variant has been submitted to ClinVar as pathogenic by seven laboratories (variation ID: 37255). Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Long QT syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 205 of the KCNQ1 protein (p.Val205Met). This variant is present in population databases (rs151344631, gnomAD 0.008%). This missense change has been observed in individuals with long QT syndrome in members of First Nation communities in British Columbia. It has been observed in the heterozygous and homozygous state in numerous affected individuals, though the severity of the symptoms was variable. In addition, this variant has been observed in unrelated individuals with long QT syndrome (PMID: 18580685, 23844633, 26669661, 27831900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37255). 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 18580685, 25444851). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2018	Variant summary: KCNQ1 c.613G>A (p.Val205Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 276590 control chromosomes. c.613G>A has been reported in the literature in multiple heterozygous individuals of whom several were affected with Long QT syndrome, as well as in four homozygous patients presenting with a more severe cardiac phenotype, and occasionally with symptoms suggestive of Jervell and Lange-Nielsen syndrome (Jackson 2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Arbour 2008). The most pronounced variant effect results in approximately 30%-50% of the normal channel activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate marked alteration of channel activity (Arbour et al., 2008; Eldstrom et al., 2010; Eldstrom et al., 2015); 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: 25637381, 22378279, 18580685, 20421371, 25525159, 23844633, 31447099, 31589614, 31737537, 28264985, 34319147, 27831900, 25444851, Sanatani2022[Article], RidaM2023[Preprint], 26669661, 32009526, 36725074) -
not provided, no classification provided	literature only	Community Genetics, University of British Columbia	-	- -

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:18580685;PMID:20421371;PMID:22378279). 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	Aug 07, 2017	The p.Val205Met variant in KCNQ1 has been reported in 2 individuals with long QT syndrome and segregated with disease in at least 10 affected relatives from bot h families (Arbour 2008). Additionally, four individuals have been reported to b e homozygous for this variant and present with a clinically more severe phenotyp e that did not include hearing loss (Jackson 2014). This variant has also been r eported by other clinical laboratories in ClinVar (variation ID: 3725) and has b een identified in 1/126300 European chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs151344631). In vitro func tional studies provide evidence that the p.Val205Met variant may impact protein function (Arbour 2008, Eldstrom 2010, Eldstrom 2015). In summary, this variant m eets criteria to be classified as pathogenic for long QT syndrome in an autosoma l dominant manner based upon segregation studies and functional evidence. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2017

The p.V205M pathogenic mutation (also known as c.613G>A), located in coding exon 4 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 613. The valine at codon 205 is replaced by methionine, an amino acid with highly similar properties. This mutation has been reported in multiple families with long QT syndrome and has been observed with an elevated prevalence in an isolated Northern Canadian population (Arbour L, Genet. Med. 2008 Jul; 10(7):545-50; Kapplinger JD et al. J. Med. Genet., 2017 Mar; Pottinger TD et al. J Am Heart Assoc, 2020 Feb;9:e013808). Additionally, in vitro studies have shown this mutant exhibits altered channel gating kinetics and currents in transfected cells (Arbour L et al. Genet. Med., 2008 Jul;10:545-50; Jackson HA, Clin. Genet. 2014 Jul; 86(1):85-90; Eldstrom J, Heart Rhythm 2015 Feb; 12(2):386-94). Based on the supporting evidence, p.V205M is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;D;N
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.92, 0.90
MVP		0.97
MPC		1.2
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.92
gMVP		0.96

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: rs151344631; hg19: chr11-2592563;