11-2527999-C-T

Position:

chr11-2527999-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000218.3(KCNQ1):c.458C>T(p.Thr153Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T153T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2O:1

Conservation

PhyloP100: 2.19

Variant links:

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 links:

KCNQ1 (HGNC:):

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21481317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.458C>T	p.Thr153Met	missense_variant	2/16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.458C>T	p.Thr153Met	missense_variant	2/16	1	NM_000218.3	ENSP00000155840.2		P51787-1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

251312

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000136

AC:

199

AN:

1461358

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000146

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000355

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000187

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS4_Moderate, PM1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 153 of the KCNQ1 protein (p.Thr153Met). This variant is present in population databases (rs143709408, gnomAD 0.05%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19716085, 25351510). ClinVar contains an entry for this variant (Variation ID: 67075). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 30571187). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces threonine with methionine at codon 153 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 the variant to result in a partially reduced sodium current density compared to the wild type (PMID: 30571187). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 19716085, 28794082, 29197658). One of these individuals carried a disease-causing variant in a different gene that could explain the observed phenotype (PMID: 28794082). This variant has also been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 23396983) and in another individual who experienced sudden unexplained death (PMID: 36293497). This variant has been identified in 49/282700 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2Other:1

not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:19716085). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26159999, 26332594, 32797034, 25637381, 22581653, 24055113, 29197658, 25351510, 19841300, 30571187, 19716085, 28988457, 35130036, 32048431, 23396983, 36293497, 28794082) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 08, 2017	p.Thr153Met (c.458C>T) in exon 2 of the KCNQ1 gene (NM_000218.2) Chromosome location 11:2549229 C / T Found in a patient with one-sided sensorineural hearing loss and atrial flutter during infancy. No confirmed diagnosis of LQTS by EKG or exercise testing. We classify this as a VUS, probably, benign, given its relatively high frequency in the broader population. Specifically, this variant has been reported in 46 individuals in the gnomAD database: 12 African-ancestry individuals (for the highest MAF: 0.05%), 28 non-Finnish European-ancestry individuals (MAF 0.02%), 3 Latinos, 2 south Asians, and 1 â€œOtherâ€ ancestry individual. Overall MAF in gnomAD is 0.017%. Of note: Whiffin et al (2017) have proposed that variants with a minor allele frequency greater than 0.0008% are unlikely to be pathogenic in LQTS. This variant has not previously been reported in a clear, clinically-confirmed case of LQTS. It was reported by Kapplinger et al. (2009) in one patient out of 2500 tested for LQTS at Familion laboratory. Of note is the lack of clinical phenotyping data on this cohort, the low genetic testing yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), indicating that some individuals in the cohort likely do not have the condition, and the lack of clarity regarding which variants were seen alongside another clearly-pathogenic variant (9% of the cohort had multiple variants). The Laboratory for Molecular Medicine at Harvard reports in ClinVar that they saw this variant in a genome or exome case but did not do a complete review. The Threonine at location 153 is not highly conserved across species. In fact, Methionine is the default amino acid in at least 1 mammalian species (elephant). There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 5 amino acids to either side, indicating that this portion of the protein might be tolerant of change. It is not entirely possible to tell from the location within the KCNQ1 protein if a variant may cause disease. When Kapa et al. (2009) compared 388 â€œclinically definiteâ€ LQTS probands to ~1300 healthy controls, they found that while controls do have variants in all regions of the protein, LQTS cases were much more likely to have missense variants in the C-terminal cytoplasmic region of the KCNQ1 protein (amino acid residues 349-676), the pore region, transmembrane region, or linker region (residues 122-348)â€”rather than in the N-terminal domain (residues 1-121). This variant does fall within the pore/transmembrance/linker region. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 31, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband; ExAC: 5/10404 African chromosomes; ClinVar: 1 VUS -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 24, 2023

This missense variant replaces threonine with methionine at codon 153 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 the variant to result in a partially reduced sodium current density compared to the wild type (PMID: 30571187). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 19716085, 28794082, 29197658). One of these individuals carried a disease-causing variant in a different gene that could explain the observed phenotype (PMID: 28794082). This variant has also been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 23396983) and in another individual who experienced sudden unexplained death (PMID: 36293497). This variant has been identified in 49/282700 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 01, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

.;D;.;.

Eigen

Benign

0.091

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.7

.;L;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.4

N;N;.;N

REVEL

Pathogenic

0.74

Sift

Benign

0.071

T;D;.;T

Sift4G

Benign

0.093

T;T;.;T

Polyphen

0.88

.;P;.;.

Vest4

0.81, 0.70

MVP

0.96

MPC

1.2

ClinPred

0.023

GERP RS

3.5

Varity_R

0.099

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over