rs199472687

Positions:

• chr11-2527962-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.421G>A​(p.Val141Met) 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 8.09

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 16 ACMG points.

• PM1: In a transmembrane_region Helical; Name=Segment S1 (size 20) in uniprot entity KCNQ1_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 11-2527962-G-A is Pathogenic according to our data. Variant chr11-2527962-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 67072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2527962-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.421G>A	p.Val141Met	missense_variant	2/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.421G>A	p.Val141Met	missense_variant	2/16	1	NM_000218.3	ENSP00000155840	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2020	Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 67072; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect as this variant results in a slowed deactivation of the potassium channel which is consistent with the disease mechanism for SQTS (Hong et al., 2005; Restier et al., 2008; Chan et al., 2012); This variant is associated with the following publications: (PMID: 24721657, 19862833, 28383569, 29697308, 24818999, 24006450, 18599533, 23375927, 16109388, 17999538, 20126594, 22529812, 26279191, 22250012, 21682648, 20667544, 26346102, 28491547, 28814790, 22581653, 25974115, 29213224, 31965297) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Short QT syndrome type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2005

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 07, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 16109388, 18599533, 24006450). 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: 67072). This missense change has been observed in individual(s) with very early onset atrial fibrillation (AF) and short QT syndrome (SQTS) (PMID: 16109388, 23375927, 24818999). In at least one individual the variant was observed to be de novo. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 141 of the KCNQ1 protein (p.Val141Met). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2016

The p.V141M pathogenic mutation (also known as c.421G>A), located in coding exon 2 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 421. The valine at codon 141 is replaced by methionine, an amino acid with highly similar properties. This mutation was reported in individuals with very early age onset atrial fibrillation (AF) and short QT syndrome (SQTS), including several reported de novo cases (Hong K et al. Cardiovasc. Res., 2005 Dec;68:433-40; Villafañe J et al. J. Am. Coll. Cardiol., 2013 Mar;61:1183-91; Harrell DT et al. Int. J. Cardiol., 2015 Apr;190:393-402; Sarquella-Brugada G et al. Heart Rhyth. Case Rpt, 2015 Jul;1:193-197). Functional studies demonstrated that this is a gain-of-function mutation resulting in slowed deactivation of the potassium channel (Hong K et al. Cardiovasc. Res., 2005 Dec;68:433-40; Restier L et al. J. Physiol. (Lond.), 2008 Sep;586:4179-91; Chan PJ et al. J. Gen. Physiol., 2012 Feb;139:135-44). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Atrial fibrillation 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 Atrial fibrillation in the following publications (PMID:16109388;PMID:18599533;PMID:22250012;PMID:17999538). 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	0.87
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	.;M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	D;D;.;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.;D;.
Sift4G	Uncertain	0.048	D;D;.;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.90, 0.86
MutPred		0.82		.;Loss of catalytic residue at V141 (P = 0.0243);.;.;.;
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.80
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199472687; hg19: chr11-2549192;