Submissions for variant NM_000218.3(KCNQ1):c.136G>A (p.Ala46Thr)

gnomAD frequency: 0.00007  dbSNP: rs199473671

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223932	SCV000234541	uncertain significance	not provided	2025-01-30	criteria provided, single submitter	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)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182238	SCV000271875	uncertain significance	not specified	2017-08-06	criteria provided, single submitter	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.
Ambry Genetics	RCV000620799	SCV000737946	uncertain significance	Cardiovascular phenotype	2021-07-29	criteria provided, single submitter	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.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678936	SCV000805148	uncertain significance	Long QT syndrome 1	2018-02-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852969	SCV002200051	uncertain significance	Long QT syndrome	2025-01-28	criteria provided, single submitter	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.
AiLife Diagnostics, AiLife Diagnostics	RCV000223932	SCV002501718	uncertain significance	not provided	2021-08-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483048	SCV002789657	uncertain significance	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-10-31	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000223932	SCV004026350	uncertain significance	not provided	2023-04-24	criteria provided, single submitter	clinical testing	PM2_SUP
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057585	SCV000089104	not provided	Congenital long QT syndrome		no assertion provided	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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223932	SCV000280143	uncertain significance	not provided	2017-11-13	no assertion criteria provided	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 time of publication. The patient’s father had WPW and underwent ablation. We have seen the variant in another family in our center. The proband was diagnosed with probable LQTS in her 40s after recurrent syncope (after one of these she was unresponsive for 2-3 minutes). It was thought her EKG and 30-day event monitor were both suspicious for long QT syndrome. She has also seen Dr. Ackerman, who recommended a switch to Nadolol. In care with Dr. Ashley she had a supine QTc of 476 ms and a standing QTc of 496 ms. Prior ECGs reviewed by Dr. Ashley showed QTc between 478 and 486 ms. Dr Perez saw her most recently and notes her QTc has only been borderline to slightly prolonged. Her son also carries the variant but reportedly has a normal QT interval. Coll et al (2016, likely redundant with Partemi et al) reported the variant in an individual with focal epilepsy and a personal or family history of SUDEP. It is unclear whether this individual had a personal or family history of SUDEP. The authors do note that a paternal grandfather died suddenly. Lieve et al (2014) report seeing this variant in two individuals. However, this is a series from GeneDx and those two individuals may be the two unrelated individuals we are aware of in our center who were tested at GeneDx. Functional data: Functional studies have suggested the variant is pathogenic via fast-activation kinetics without an initial delay at the beginning phase of the Iks (Rees et al 2009). Steffensen et al (2015) studied the variant in vitro and observed a gain of function in the IKs. Notably, gain-of-function is not a known mechanism for LQT1. In silico, conservation: In silico analysis with PolyPhen-2 predicts the variant to be benign The alanine at codon 46 is not conserved across species and isoforms and is in fact at threonine in rats. This is a non-conservative amino acid change from hydrophobic to hydrophytic residue. No other variants have been reported in association with disease at this codon. The variant falls in the amino-terminal region of the protein; only a few other variants have been reported in association with disease in that region. Variants at the corresponding codon in the paralogue KCNC3 have been associated with Spinocerebellar ataxia 13 (http://cardiodb.org/Paralogue_Annotation/residue.php?gene=KCNQ1&position=46). Population frequency: Unfortunately there is poor coverage in both ExAC and gnomAD. Per varsome, only 0.85% of ExAC exomes and 58.73% of gnomAD genomes have coverage >20x. GnomAD notes the following warning: "This variant is only covered in 8215 individuals (adjusted allele number = 16430). This means that the site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site." In the ExAC exomes that passed their quality filters it was seen in 1 in 3055 Europeans (MAF 0.01637%). GeneDx did not observe it in 273 individuals. The variant was not observed in the following published control samples : 400 (Napolitano et al 2005), 100 (Chung et al 2007), 1300 (Kapplinger et al 2009), 200 (Olesen et al 2011).