rs199472678

Positions:

• chr11-2445430-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001406837.1(KCNQ1):​c.-31A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000346 in 1,445,536 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: KCNQ1 NM_001406837.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 6.18

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 11-2445430-A-G is Pathogenic according to our data. Variant chr11-2445430-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 53035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2445430-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.332A>G	p.Tyr111Cys	missense_variant	1/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.332A>G	p.Tyr111Cys	missense_variant	1/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000345015.4	n.109A>G		non_coding_transcript_exon_variant	1/3	1
KCNQ1	ENST00000496887.7	c.71A>G	p.Tyr24Cys	missense_variant	2/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.332A>G	p.Tyr111Cys	missense_variant	1/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000894 AC: 2 AN: 223694 Hom.: 0 AF XY: 0.0000161 AC XY: 2 AN XY: 124078

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: 0.0000199

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1445536 Hom.: 0 Cov.: 31 AF XY: 0.00000556 AC XY: 4 AN XY: 719524

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000168 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	KCNQ1: PP1:Strong, PM1, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2022	Haplotype analysis was performed using a cohort of 26 Swedish probands, 21 family members, and 84 healthy controls; the authors concluded the Y111C variant originated 600 years ago in the Northern River Valley population (Winbo et al., 2011); Reported to be homozygous in a female with JLNS (Winbo et al., 2012); Identified in numerous patients referred for LQTS genetic testing at GeneDx; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Functional studies have demonstrated that Y111C, which is located in the N-terminal region of the protein, alters a motif that plays a key role in intracellular trafficking of the potassium channel, thus trapping the protein in the endoplasmic reticulum and rendering the channels inactive (Dahimene et al., 2006; Peroz et al., 2009, Winbo et al., 2009; Lee et al., 2020); This variant is associated with the following publications: (PMID: 19008479, 23098067, 27936942, 30847666, 24052033, 19114714, 17053194, 19716085, 20031635, 10973849, 28720088, 30571187, 26019114, 22581653, 22539601, 29532034, 21129503, 29270100, 32383558, 32173736, 33963564, 34761968, 34505893) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 13, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Tyr111Cys This variant has been reported in at least 46 unrelated cases with Long QT Syndrome, with strong segregation data in a founder population. Splawski et al (2000) first reported p.Tyr111Cys in a 36 yo North American female who presented with a history of over 30 syncopal episodes and a QTC of 520ms. The syncopal episodes were triggered by stress. In 2009 Kapplinger et al reported 5 unrelated case with the variant out or 2500 cases sent to Transgenomic Labs for testing between May 2004 and October 2008. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). That same year Winbo et al (2009) reported of 15 probands with the variant and 80 related carriers (mean QTc 481ms with prolonged QTc in 86% of carriers), all were of Swedish descent. Winbo et al demonstrated that p.Tyr111Cys is a founder mutation in the Swedish population. Two years later Winbo et al (2011) reported 37 unrelated cases with p.Tyr111Cys and a total of 170 carriers (cases presumably overlap with WInbo et al 2009, Diamant et al 2013, by the same group). The same group reported that p.Tyr111Cys was observed in 20 of 200 unrelated long QT cases (presumably overlapping with their other reported cases). Winbo et al (2009) found that the event rate was lower in carriers of p.Tyr111Cys than in other KCNQ1 carriers. The Swedish group also reported a patient with JLNS who was homozygous for this variant (Winbo et al 2012). Ackerman’s group observed the variant in a 3yo that died suddenly in his sleep, with a history of syncope and a negative autopsy. Laksman et al (2014) report a patient with long QT and this variant, however sequencing was done in a clinical genetic testing lab so that may overlap with the Kapplinger et al (2009) cases. Crotti et al (2012) reported two unrelated individuals with this variant recruited in either Italy or South Africa, however it is not clear if they have phenotypic evidence of long QT syndrome. This is a semi conservative amino acid change with a large, polar Tyrosine replaced with a medium sized, polar Cysteine. The amino acid change occurs at the N-terminal of the KCNQ1 protein. In silico (SIFT, PolyPhen 2) analysis predict the amino acid change to be deleterious and probably damaging to the resulting protein. Missense variants in nearby codons (p.His105Leu, p.Leu114Pro, p.Glu115Gly, p.Pro117Leu) have been reported in association with LQTS. This variant is listed in the hearing.harvard database. There are no functional studies involving mouse models. However Dahieme et al (2006) did show that cardiomyocites with the variant have impaired protein trafficking and malfunctioning potassium channel subunits. In total the variant has not been seen in ~8300 individuals from published control samples and publicly available general population datasets. Splawski et al (2000) report that p.Tyr111Cys was absent in 200 presumably healthy controls whose ancestry was not specified. Kapplinger et al (2009) reported that p.Tyr111Cys was not observed in 1300 presumably healthy controls (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). Tester et al (2012) did not observe the variant in and additional 200 controls. The variant was not observed by Stattin et al (2012) in 100 Swedish controls. The variant is listed in dbSNP with the rs199472678 with submission only from a locus-specific database; there is no allele frequency data available. The v -

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 09, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome 2 (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome 1 (LQTS, MIM#192500), familial atrial fibrillation 3 (MIM#607554) as well as Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterised by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (5 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Pathogenic missense variants are seen to cluster in the juxtamembranous region just preceding the first transmembrane domain (PMID:17053194, DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Tyr111Ser) has been reported once as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by five clinical testing laboratories (ClinVar) and has been reported in many individuals with LQTS. Additionally, this variant has been referred to as a founder variant in the Swedish population; however, it has also been reported in non-Swedish individuals (PMIDs: 20031635, 25929701, 23158531). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro analysis demonstrates this variant exerts a dominant negative effect that results in a channel trafficking defect (PMID:17053194). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 30, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 111 of the KCNQ1 protein (p.Tyr111Cys). This variant is present in population databases (rs199472678, gnomAD 0.002%). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 10973849, 20031635, 21129503, 22539601). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53035). 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: 17053194, 19114714, 29532034). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2018

The p.Y111C pathogenic mutation (also known as c.332A>G), located in coding exon 1 of the KCNQ1 gene, results from an A to G substitution at nucleotide position 332. The tyrosine at codon 111 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in numerous individuals with long QT syndrome and is a founder mutation in the Swedish population (Splawski I et al. Circulation, 2000 Sep;102:1178-85; Dahimène S et al. Circ. Res., 2006 Nov;99:1076-83; Winbo A et al. Circ Cardiovasc Genet, 2009 Dec;2:558-64; Winbo A et al. Europace, 2012 Dec;14:1799-806; Stattin EL et al. BMC Cardiovasc Disord, 2012 Oct;12:95). In addition, this mutation was identified in the homozygous state in an individual with Jervell and Lange-Nielsen Syndrome (Winbo A et al. Circ Arrhythm Electrophysiol, 2015 Aug;8:806-14). Functional studies have demonstrated that this mutation results in no cell surface expression or potassium current, with the protein retained in the endoplasmic reticulum which is degraded more rapidly compared to wild type (Peroz D et al. J. Biol. Chem., 2009 Feb;284:5250-6; Dahimène S et al. Circ. Res., 2006 Nov;99:1076-83). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:10973849;PMID:17053194;PMID:19114714;PMID:19716085;PMID:20031635;PMID:21129503;PMID:22539601). 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	0.95
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	2.0	.;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.96
MutPred		0.89		.;Gain of helix (P = 0.0696);
MVP		0.99
MPC		2.5
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.97
gMVP		0.99

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: rs199472678; hg19: chr11-2466660;