rs199472687

Variant names:

• chr11-2527962-G-A
• rs199472687
• NM_000218.3:c.421G>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:8 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 helix (size 21) 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 rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.421G>A	p.Val141Met	missense_variant	Exon 2 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.421G>A	p.Val141Met	missense_variant	Exon 2 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 17, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Short QT syndrome type 2 Pathogenic:1

Dec 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

KCNQ1-related disorder Pathogenic:1

Oct 28, 2023

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.421G>A (p.Val141Met) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported in patients with atrial fibrillation and short QT syndrome (PMID: 16109388, 23375927, 25974115). Functional studies illustrate that is a gain of function variant that affects KCNQ1 function (PMID: 16109388, 18599533, 22250012, 24006450). The c.421G>A (p.Val141Met) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, c.421G>A (p.Val141Met) is classified as Pathogenic. -

Long QT syndrome Pathogenic:1

Mar 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 67072). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 16109388, 18599533, 24006450). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Dec 02, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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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 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;.;.;.
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;