ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.136G>A (p.Ala46Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000218.3(KCNQ1):c.136G>A (p.Ala46Thr)
Variation ID: 52982 Accession: VCV000052982.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2445234 (GRCh38) [ NCBI UCSC ] 11: 2466464 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 9, 2016 Feb 20, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.136G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Ala46Thr missense NC_000011.10:g.2445234G>A NC_000011.9:g.2466464G>A NG_008935.1:g.5244G>A LRG_287:g.5244G>A LRG_287t1:c.136G>A LRG_287p1:p.Ala46Thr P51787:p.Ala46Thr - Protein change
- A46T
- Other names
- p.A46T:GCG>ACG
- Canonical SPDI
- NC_000011.10:2445233:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00006
The Genome Aggregation Database (gnomAD) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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KCNQ1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1648 | 2513 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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not provided (1) |
no classification provided
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- | RCV000057585.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 6, 2017 | RCV000182238.10 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Sep 26, 2023 | RCV000223932.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 29, 2021 | RCV000620799.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 23, 2018 | RCV000678936.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 19, 2023 | RCV001852969.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2021 | RCV002483048.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jul 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000737946.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.A46T variant (also known as c.136G>A), located in coding exon 1 of the KCNQ1 gene, results from a G to A substitution at nucleotide … (more)
The p.A46T variant (also known as c.136G>A), located in coding exon 1 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 136. The alanine at codon 46 is replaced by threonine, an amino acid with similar properties, and is located in the cytoplasmic N-terminal region. This alteration has been previously reported in long QT syndrome (LQTS), atrial fibrillation (AF), and epilepsy cohorts; however, clinical details were limited (Napolitano C et al. JAMA. 2005;294:2975-80; Chung SK et al. Heart Rhythm. 2007;4:1306-14; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61; Olesen MS et al. Heart Rhythm. 2014;11:246-51; Partemi S et al. Int. J. Legal Med. 2015;129:495-504; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). In vitro functional studies suggest that this alteration causes a gain of KCNQ1 channel function, but the physiological relevance of these results is unclear (Yang T et al. Circ Arrhythm Electrophysiol. 2009;2:417-26; Steffensen AB et al. J. Cardiovasc. Electrophysiol. 2015;26:715-23). This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Oct 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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Beckwith-Wiedemann syndrome
Long QT syndrome 1 Long QT syndrome 1 Jervell and Lange-Nielsen syndrome 1 Atrial fibrillation, familial, 3 Short QT syndrome type 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002789657.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Feb 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV000805148.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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Uncertain significance
(Aug 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271875.2
First in ClinVar: May 29, 2016 Last updated: Apr 09, 2018 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Aug 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501718.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Uncertain significance
(Apr 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026350.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PM2_SUP
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Uncertain significance
(Sep 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000234541.16
First in ClinVar: Jul 05, 2015 Last updated: Nov 25, 2023 |
Comment:
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., … (more)
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) (less)
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Uncertain significance
(Dec 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002200051.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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. (less)
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Uncertain significance
(Nov 13, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280143.2
First in ClinVar: Jun 03, 2016 Last updated: Nov 08, 2018 |
Comment:
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 … (more)
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). (less)
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089104.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
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 … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region. | Schwartz PJ | European heart journal | 2021 | PMID: 34505893 |
Disease-linked supertrafficking of a potassium channel. | Huang H | The Journal of biological chemistry | 2021 | PMID: 33600800 |
Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes. | Diebold I | Human mutation | 2020 | PMID: 32048431 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing. | Coll M | International journal of legal medicine | 2016 | PMID: 26423924 |
IKs Gain- and Loss-of-Function in Early-Onset Lone Atrial Fibrillation. | Steffensen AB | Journal of cardiovascular electrophysiology | 2015 | PMID: 25786344 |
Genetic and forensic implications in epilepsy and cardiac arrhythmias: a case series. | Partemi S | International journal of legal medicine | 2015 | PMID: 25119684 |
Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation. | Olesen MS | Heart rhythm | 2014 | PMID: 24144883 |
Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. | Lieve KV | Genetic testing and molecular biomarkers | 2013 | PMID: 23631430 |
Genotype- and Sex-Specific QT-RR Relationship in the Type-1 Long-QT Syndrome. | Couderc JP | Journal of the American Heart Association | 2012 | PMID: 23130128 |
Elevated serum gastrin levels in Jervell and Lange-Nielsen syndrome: a marker of severe KCNQ1 dysfunction? | Rice KS | Heart rhythm | 2011 | PMID: 21118729 |
Biophysical properties of 9 KCNQ1 mutations associated with long-QT syndrome. | Yang T | Circulation. Arrhythmia and electrophysiology | 2009 | PMID: 19808498 |
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. | Kapplinger JD | Heart rhythm | 2009 | PMID: 19716085 |
Long QT and Brugada syndrome gene mutations in New Zealand. | Chung SK | Heart rhythm | 2007 | PMID: 17905336 |
Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. | Napolitano C | JAMA | 2005 | PMID: 16414944 |
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Text-mined citations for rs199473671 ...
HelpRecord last updated Feb 28, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.