rs143709408

chr11-2527999-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 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 Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2 O:1
• Conservation: PhyloP100: 2.19

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000218.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.21481317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.458C>T	p.Thr153Met	missense_variant	2/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.458C>T	p.Thr153Met	missense_variant	2/16	1	NM_000218.3	P1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152206 Hom.: 0 Cov.: 34

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: 40 AN: 251312 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135852

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.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 727030

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: 54 AN: 152324 Hom.: 0 Cov.: 34 AF XY: 0.000376 AC XY: 28 AN XY: 74472

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.: 0

Bravo AF: 0.000355

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:4

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS4_Moderate, PM1 -

not provided Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2018	The T153M variant of uncertain significance in the KCNQ1 gene has been previously reported in one individual referred for LQTS genetic testing; however, no clinical details or segregation data were provided (Kapplinger et al., 2009). This variant has also been identified in two families referred for arrhythmia genetic testing at GeneDx; however, at least one of these individuals was found to harbor an additional cardiogenetic variant, and segregation data is limited for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. In addition, T153M has been observed in 0.05% (5/10,404) and 0.02% (14/66,708) of alleles from individuals of African and European (Non-Finnish) background, respectively, in the Exome Aggregation Consortium data set (Lek et al., 2016). Moreover, while T153M is conserved in mammals, M153 is tolerated in at least one mammalian species. Nevertheless, T153M is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.Furthermore, the majority of in silico algorithms predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time. -
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, 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 “Other” 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 “clinically definite” 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)—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
CardioboostArm	Uncertain	0.55
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	0.091
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Pathogenic	0.85	D
MutationTaster	Benign	0.87	D;D
PrimateAI	Uncertain	0.64	T
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	T
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

Other links and lift over

dbSNP: rs143709408; hg19: chr11-2549229; COSMIC: COSV50140712; COSMIC: COSV50140712;