rs199473671

Positions:

• chr11-2445234-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.136G>A	p.Ala46Thr	missense_variant	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.136G>A	p.Ala46Thr	missense_variant	1/15
KCNQ1	NM_001406838.1	c.136G>A	p.Ala46Thr	missense_variant	1/11
KCNQ1	NM_001406837.1	c.-227G>A		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.136G>A	p.Ala46Thr	missense_variant	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000646564.2	c.136G>A	p.Ala46Thr	missense_variant	1/11
KCNQ1	ENST00000496887.7	c.24-149G>A		intron_variant		5

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

GnomAD3 exomes AF: 0.0000600 AC: 1 AN: 16670 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10080

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: 0.000163

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

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: 0.0000741

Gnomad4 OTH exome AF: 0.0000277

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000165

Gnomad4 OTH AF: 0.00

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

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2023	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); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); 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, 26423924, 34505893, 23130128) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Apr 24, 2023	PM2_SUP -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 24, 2021	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 13, 2017	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 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 06, 2017

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. -

Long QT syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 23, 2018

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2021

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

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). 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: 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2021

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

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: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
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
MutationTaster	Benign	1.0	N
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
Varity_R		0.035
gMVP		0.26

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: rs199473671; hg19: chr11-2466464;