rs199472722

Variant names:

• chr11-2572846-G-A
• rs199472722
• NM_000218.3:c.781G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2572846-G-A
• chr11-2572846-G-C
• chr11-2572846-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.781G>A​(p.Glu261Lys) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E261D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense, splice_region
• Scores: Splicing: ADA: 0.9111
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.21

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 18 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 12) in uniprot entity KCNQ1_HUMAN there are 20 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 chr11-2572848-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 11-2572846-G-A is Pathogenic according to our data. Variant chr11-2572846-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572846-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.781G>A	p.Glu261Lys	missense_variant, splice_region_variant	Exon 6 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.781G>A	p.Glu261Lys	missense_variant, splice_region_variant	Exon 6 of 16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.400G>A	p.Glu134Lys	missense_variant, splice_region_variant	Exon 6 of 16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.520G>A	p.Glu174Lys	missense_variant, splice_region_variant	Exon 7 of 16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-10589G>A		intron_variant	Intron 2 of 10			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:1

Aug 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 261 of the KCNQ1 protein (p.Glu261Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with prolonged QT interval (PMID: 9386136; Invitae). ClinVar contains an entry for this variant (Variation ID: 53103). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 10409658, 15935335). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Glu261 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10704188, 11530100, 15935335, 26675252; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jan 17, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E261K variant (also known as c.781G>A) is located in coding exon 6 of the KCNQ1 gene. The glutamic acid at codon 261 is replaced by lysine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 6. This variant has been reported in individuals with features consistent with long QT syndrome (Donger C et al. Circulation, 1997 Nov;96:2778-81; Schwartz PJ et al. Eur Heart J, 2021 Dec;42:4743-4755; Singer ES et al. NPJ Genom Med, 2023 Oct;8:29; Ambry internal data). In assays testing KCNQ1 function, this variant showed functionally abnormal results (Franqueza L et al. J Biol Chem, 1999 Jul;274:21063-70; Wilson AJ et al. Cardiovasc Res, 2005 Aug;67:476-86; Hou P et al. Nat Commun, 2020 Feb;11:676). RNA studies by one group indicated that this variant may result aberrant splicing (Singer ES et al. NPJ Genom Med, 2023 Oct;8:29). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

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:9386136;PMID:10409658;PMID:15935335). 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	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.99, 0.94
MutPred		0.91		.;Loss of helix (P = 0.0138);.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.76		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199472722; hg19: chr11-2594076;