rs199473671

Variant names:

• chr11-2445234-G-A
• rs199473671
• NM_000218.3:c.136G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000218.3(KCNQ1):​c.136G>A​(p.Ala46Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000673 in 1,143,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9 O:1
• Conservation: PhyloP100: 0.596
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.136G>A	p.Ala46Thr	missense_variant	Exon 1 of 16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1	c.136G>A	p.Ala46Thr	missense_variant	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1	c.136G>A	p.Ala46Thr	missense_variant	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1	c.-227G>A		5_prime_UTR_variant	Exon 1 of 17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.136G>A	p.Ala46Thr	missense_variant	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.0000742 AC: 11 AN: 148180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000165

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000600 AC: 1 AN: 16670 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000663 AC: 66 AN: 995216 Hom.: 0 Cov.: 30 AF XY: 0.0000588 AC XY: 28 AN XY: 476588

African (AFR) AF: 0.00 AC: 0 AN: 19306

American (AMR) AF: 0.00 AC: 0 AN: 8196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10502

East Asian (EAS) AF: 0.00 AC: 0 AN: 14480

South Asian (SAS) AF: 0.00 AC: 0 AN: 25512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14724

Middle Eastern (MID) AF: 0.000418 AC: 1 AN: 2392

European-Non Finnish (NFE) AF: 0.0000741 AC: 64 AN: 863946

Other (OTH) AF: 0.0000277 AC: 1 AN: 36158

GnomAD4 genome AF: 0.0000742 AC: 11 AN: 148180 Hom.: 0 Cov.: 32 AF XY: 0.0000416 AC XY: 3 AN XY: 72154

African (AFR) AF: 0.00 AC: 0 AN: 41004

American (AMR) AF: 0.00 AC: 0 AN: 14932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000165 AC: 11 AN: 66472

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000945

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Jan 30, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple individuals referred for long QT syndrome genetic testing in the literature (Napolitano et al., 2005; Chung et al., 2007; Kapplinger et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21118729, 19716085, Pelletti2020[abstract], 16414944, 24144883, 25786344, 17905336, 25119684, 23631430, 28595573, 19808498, 32048431, 31737537, 30847666, 33600800, 34505893, 26423924, 23130128, 39244732) -

Nov 13, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

KCNQ1 p.Ala46Thr (c.136 G>A) Case data: The variant has been seen in: -2 case of LQTS -2-3 cases of possible LQTS – 1 in our center, 1-2 from the Familion cohort -1 case of syncope and QT-prolongation in the setting of a QT-prolonging medication with a family history of young sudden death and syncope. Other relatives with syncope did not have prolonged QT intervals and the variant did not segregate with syncope in the family. -1 case of early-onset atrial fibrillation with non-sustained ventricular tachycardia, inducible polymorphic and monomorphic ventricular tachycardia and an ejection fraction of 50% -1 case of focal epilepsy with a personal or family history of SUDEP. Long QT cases: Napolitano et al (2005) reported the variant in a list of novel variants observed in their Italian cohort of long QT syndrome patients. Robyn Hylind shared that they have seen this variant in a patient with LQTS in their center (children's hospital boston). The patient was also worked up at CHOP and Yale and had clinical genetic testing so there may be redundancy with other cases (I counted this case in the summary above and reduced the Familion count, suspecting the patient was tested there). The proband presented at 5yo with recurrent syncope, QTc 500 ms, QTc 550 ms on exercise testing. Brother is a carrier and has a QTc of 380 ms. Borderline or other phenotypes: Chung et al (2007) observed the variant in one individual with syncope, a prolonged QTc (in the setting of Cisapride, which is QT-prolonging), and a family history of sudden death in their cohort from New Zealand. The same group later published what appears to be additional data on the same patient that may be suggestive of failure to segregate or perhaps even that long QT is not the right phenotype (Yang et al 209). Two other family members have the variant, a history of syncope, and maximal QTc intervals of 440 ms (in a female) and 420 ms (in a male). Another family member has a history of syncope and a maximal QTc of 440 ms but doesn't have the variant. The authors note they are not using the variant for cascade screening. I suspect the same family is reported in Rice et al (2011). I connect with Dr. Jon Skinner, who leads this group. He re-reviewed the case and noted he thinks it is most likely a VUS and that the original exercise data supporting long QT is perhaps not very strong and may in fact be normal. The variant was observed in two different patients in the Familion/PGxHealth published cohort (Kapplinger et al 2009), which includes 2500 patients referred for clinical long QT genetic testing. Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. 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). These cases are likely redundant with Aziz et al (2011) as they report doing testing through Familion/PGxHealth. They do not provide any additional phenotypic detail and the inclusion criteria for the study did not include clearly abnormal QT length. Steffensen et al (2015) report the variant in an individual with atrial fibrillation onset at 38yo, a normal QTc (428 ms), and non-sustained ventricular tachycardia, recruited in Denmark (presumably redundant with Olesen et al 2014 and meeting abstract by Olesen et al). Work-up was extensive including coronary angiography, cardiac MRI, echocardiogram, stress test, and myocardial biopsy. Echo showed ejection fraction of 50% with no other abnormalities found. On EP study there was inducible polymorphic ventricular tachycardia, monomorphic ventricular tachycardia, and atrial fibrillation. An ICD was placed but had not discharged by -

Apr 24, 2023

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_SUP -

Aug 24, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome 1 Uncertain:1

Feb 23, 2018

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Aug 06, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala46Thr variant in KCNQ1 has not been previously reported in individuals with hearing loss or Jervell and Lange-Nielsen syndrome, but has been identified in 1 individual with early onset (<40 years) atrial fibrillation (Olesen 2014), in 1 individual with focal epilepsy (Partemi 2015), in 2 individuals with long QT syndrome (Kaplinger 2009), and in 1 individual with suspected LQTS and syncop e (Chung 2007, Yang 2009). However, the individual with suspected LQTS and synco pe had 3 relatives with syncope without LQTS, and only 2 of 3 of these relatives carried the variant (Yang 2009). This variant was absent in 3500 control chromo somes reported in three studies (Napolitano 2005, Chung 2007, Kapplinger 2009) a nd absent from the gnomAD database. In-vitro functional studies provided inconcl usive evidence on the impact of this variant on normal protein function (Yang 20 09). In addition, alanine (Ala) at position 46 is not conserved through species, with 1 mammal (rat) having a threonine (Thr) at this position, suggesting that variants at this position may be tolerated. In summary, due to conflicting data, the clinical significance of the p.Ala46Thr variant is uncertain. -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Uncertain:1

Oct 31, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 46 of the KCNQ1 protein (p.Ala46Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with lone atrial fibrillation and/or long QT syndrome (PMID: 16414944, 17905336, 19808498, 21118729, 23130128, 24144883, 25786344, 30847666, 31737537, 34505893). ClinVar contains an entry for this variant (Variation ID: 52982). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNQ1 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 19808498, 33600800). 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. -

Cardiovascular phenotype Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.136G>A (p.A46T) alteration is located in exon 1 (coding exon 1) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the alanine (A) at amino acid position 46 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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:16414944;PMID:17905336;PMID:19716085;PMID:19808498). 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	Benign	0.071
CardioboostArm	Benign	0.0027
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.55	N
PhyloP100		0.60
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.52
Sift	Benign	0.28	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.67
MVP		0.88
MPC		1.1
ClinPred		0.055	T
GERP RS		1.4
PromoterAI		-0.080	Neutral
Varity_R		0.035
gMVP		0.26
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs199473671; hg19: chr11-2466464;