rs120074177

chr11-2570682-G-Achr11-2570682-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_000218.3(KCNQ1):c.532G>A(p.Ala178Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,459,952 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A178G?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1 O:1
• Conservation: PhyloP100: 6.08

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 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2570683-C-GG is described in ClinVar as [Pathogenic]. Clinvar id is 53062.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 11-2570682-G-A is Pathogenic according to our data. Variant chr11-2570682-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570682-G-A is described in Lovd as [Pathogenic]. Variant chr11-2570682-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.532G>A	p.Ala178Thr	missense_variant	3/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.532G>A	p.Ala178Thr	missense_variant	3/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.151G>A	p.Ala51Thr	missense_variant	3/16	1
KCNQ1	ENST00000496887.7	c.271G>A	p.Ala91Thr	missense_variant	4/16	5
KCNQ1	ENST00000646564.2	c.478-12753G>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248870 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135094

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1459952 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 27, 2020	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1_MOD,PM2,PS4_SUP,PP3. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene, however only missense causing short QT syndrome has been reported with a gain of function mechanism (OMIM). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Both truncating variants escaping NMD, and missense have been proven to cause a dominant negative effect (OMIM, PMID: 19632626). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Recessive disease is mostly caused by biallelic NMD variants (PMID: 28438721). (N) 0112 - Variants in this gene causing long QT syndrome are known to have reduced penetrance (GeneReviews, OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine (exon 3). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif, (S2 to S3 intracellular linker within the ion transporter domain; NCBI). (N) 0704 - Comparable variant (p.Ala178Pro) has low previous evidence for pathogenicity in patients with long QT syndrome (ClinVar, LOVD, PMID: 19490272). (P) 0801 - Strong previous evidence of pathogenicity in unrelated heterozygous and homozygous individuals with long QT syndrome. Heterozygous carriers have been reported as both symptomatic and asymptomatic (ClinVar, LOVD, PMID: 28438721, PMID: 19716085, PMID: 9024139, PMID: 30530868) (P) 1002 - Moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated impaired protein localization and shifts to depolarized potentials (PMID: 24912595). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	KCNQ1: PS2, PM5, PS4:Moderate, PM2:Supporting, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2022	Identified in several patients with LQTS referred for genetic testing at GeneDx and in published literature (Tanaka et al., 1997; Splawski et al., 2000; Jons et al., 2009; Kapplinger et al., 2009; Kwok et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant severely disrupts channel trafficking (Harmer et al., 2014; Mousavi 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: 10973849, 25705178, 30530868, 22378279, 25637381, 22456477, 9024139, 12388934, 19490272, 26546361, 28991257, 19716085, 32368696, 34426522, 24912595) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 30, 2021	PS3, PM2, PM1, PP3 -

Long QT syndrome Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 178 of the KCNQ1 protein (p.Ala178Thr). This variant is present in population databases (rs120074177, gnomAD 0.003%). This missense change has been observed in individuals with long QT syndrome (PMID: 9024139, 10973849, 19716085, 22456477). ClinVar contains an entry for this variant (Variation ID: 53061). 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: 24912595). This variant disrupts the p.Ala178 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17470695). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Aug 19, 2019

This c.532G>A (p.Ala178Thr) variant in the KCNQ1 gene has been reported in patients with Long QT syndrome (PMID: 9024139, 22456477, 10973849). This variant has an ultra-low minor allele frequency in the gnomAD database (1/248870). The Ala178 residue is highly conserved and multiple computational algorithms predict a deleterious effect of the p.Ala178Thr change. In vitro functional studies suggest this variant disrupts channel trafficking (PMID: 24912595). Therefore, the c.532G>A (p.Ala178Thr) variant in the KCNQ1 gene is classified as likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

The p.A178T variant (also known as c.532G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 532. The alanine at codon 178 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in individuals reported to have long QT syndrome (Tanaka T et al. Circulation. 1997; 95(3):565-7 (reported as Ala49Thr); Jons C et al. J Cardiovasc Electrophysiol. 2009; 20(8):859-65; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). In one study, this alteration was detected as compound heterozygous with a frameshift alteration in a severely affected child, while relatives who were heterozygous for this alteration was unaffected. In the same study, the p.A178T alteration was reported to have moderate impact on channel trafficking and function and moderate dominant negative effect (Harmer SC et al. Biochem J. 2014; 462(1):133-42). 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. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 07, 2022

This missense variant replaces alanine with threonine at codon 178 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in the protein retention in the endoplasmic reticulum and a reduced cell-surface expression of the potassium channel due to the trafficking defects (PMID: 24912595). This variant has been reported in at least ten unrelated individuals affected with long QT syndrome (PMID: 9024139, 10973849, 19490272, 19716085, 22456477, 28438721, 29033053, 30530868, 32893267). Of these, 3 affected individuals were homozygous for this variant. Two related homozygous individuals were affected with Long QT syndrome at childhood while one heterozygous individual from the same consanguineous family was unaffected at the age of 39 (PMID: 28438721). Another unrelated homozygous individual was affected with autosomal recessive Romano-Ward Syndrome (PMID: 29033053). This variant has also been observed in compound heterozygous state with a pathogenic truncation variant in a child affected with severe phenotype (PMID: 24912595). This variant has been identified in 1/248870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

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:9024139;PMID:19716085;PMID:22378279). 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	0.88
CardioboostArm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.94, 0.94
MVP		0.97
MPC		1.1
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.87
gMVP		0.94

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: rs120074177; hg19: chr11-2591912;