ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.964A>G (p.Thr322Ala)
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.964A>G (p.Thr322Ala)
Variation ID: 53149 Accession: VCV000053149.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2583477 (GRCh38) [ NCBI UCSC ] 11: 2604707 (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 14, 2024 May 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.964A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Thr322Ala missense NM_001406836.1:c.964A>G NP_001393765.1:p.Thr322Ala missense NM_001406837.1:c.694A>G NP_001393766.1:p.Thr232Ala missense NM_001406838.1:c.520A>G NP_001393767.1:p.Thr174Ala missense NM_181798.2:c.583A>G NP_861463.1:p.Thr195Ala missense NR_040711.2:n.857A>G NC_000011.10:g.2583477A>G NC_000011.9:g.2604707A>G NG_008935.1:g.143487A>G LRG_287:g.143487A>G LRG_287t1:c.964A>G LRG_287p1:p.Thr322Ala LRG_287t2:c.583A>G LRG_287p2:p.Thr195Ala P51787:p.Thr322Ala - Protein change
- T322A, T195A, T174A, T232A
- Other names
- p.T322A:ACG>GCG
- Canonical SPDI
- NC_000011.10:2583476:A:G
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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.
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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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
1696 | 2580 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
Help
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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- | RCV000057829.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 14, 2022 | RCV000182147.10 | |
Pathogenic (1) |
criteria provided, single submitter
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May 16, 2020 | RCV001258360.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 25, 2022 | RCV001386679.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 28, 2023 | RCV002381344.2 |
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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Pathogenic
(Jan 07, 2022)
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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: SCV000234450.16
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in suppression of the … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in suppression of the potassium current (Burgess et al., 2012; Rothenberg et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 53149); This variant is associated with the following publications: (PMID: 24269949, 15851119, 15840476, 23092362, 19815527, 19716085, 22949429, 12877697, 22199116, 19841300, 15466642, 28491751, 31737537, 32383558, 30219255) (less)
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Pathogenic
(Oct 25, 2022)
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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: SCV001587011.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the p.Thr322 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16414944, 17470695, … (more)
This variant disrupts the p.Thr322 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16414944, 17470695, 18400097, 19716085, 23092362). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 23092362, 28491751). 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) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. ClinVar contains an entry for this variant (Variation ID: 53149). This missense change has been observed in individuals with long QT syndrome (LQTS) (PMID: 19716085, 22949429, 23092362). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 322 of the KCNQ1 protein (p.Thr322Ala). (less)
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Pathogenic
(May 16, 2020)
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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: SCV001435327.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
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Likely pathogenic
(May 28, 2023)
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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: SCV002693863.2
First in ClinVar: Nov 29, 2022 Last updated: Jul 08, 2023 |
Comment:
The p.T322A variant (also known as c.964A>G), located in coding exon 7 of the KCNQ1 gene, results from an A to G substitution at nucleotide … (more)
The p.T322A variant (also known as c.964A>G), located in coding exon 7 of the KCNQ1 gene, results from an A to G substitution at nucleotide position 964. The threonine at codon 322 is replaced by alanine, an amino acid with similar properties, and is located in the transmembrane spanning pore/S6 region of the protein. This alteration has been reported in individuals with long QT syndrome (Nemec J et al. Pacing Clin Electrophysiol, 2003 Aug;26:1660-7; Choi G et al. Circulation, 2004 Oct;110:2119-24; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Giudicessi JR et al. Circ Cardiovasc Genet, 2012 Oct;5:519-28; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Westphal DS et al. Mol Genet Genomic Med, 2020 09;8:e1300). Additionally, in vitro studies suggest that this alteration results in abnormal protein function (Burgess DE et al. Biochemistry, 2012 Nov;51:9076-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Apr 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226840.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM2, PS3, PS4
Number of individuals with the variant: 1
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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: SCV000089349.3
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:12877697;PMID:15466642;PMID:15840476;PMID:19716085;PMID:19841300). 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:12877697;PMID:15466642;PMID:15840476;PMID:19716085;PMID:19841300). 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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Reclassification of genetic variants in children with long QT syndrome. | Westphal DS | Molecular genetics & genomic medicine | 2020 | PMID: 32383558 |
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 |
Prevalence and clinical phenotype of concomitant long QT syndrome and arrhythmogenic bileaflet mitral valve prolapse. | Giudicessi JR | International journal of cardiology | 2019 | PMID: 30219255 |
Structural interplay of K(V)7.1 and KCNE1 is essential for normal repolarization and is compromised in short QT syndrome 2 (K(V)7.1-A287T). | Rothenberg I | HeartRhythm case reports | 2016 | PMID: 28491751 |
High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K(+) permeation. | Burgess DE | Biochemistry | 2012 | PMID: 23092362 |
Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. | Giudicessi JR | Circulation. Cardiovascular genetics | 2012 | PMID: 22949429 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
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 |
Prevalence of early-onset atrial fibrillation in congenital long QT syndrome. | Johnson JN | Heart rhythm | 2008 | PMID: 18452873 |
Identification of a novel KCNQ1 mutation associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome in a Chinese family. | Zhang S | BMC medical genetics | 2008 | PMID: 18400097 |
Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. | Moss AJ | Circulation | 2007 | PMID: 17470695 |
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 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Identification of a common genetic substrate underlying postpartum cardiac events in congenital long QT syndrome. | Khositseth A | Heart rhythm | 2004 | PMID: 15851119 |
Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. | Choi G | Circulation | 2004 | PMID: 15466642 |
Catecholamine-provoked microvoltage T wave alternans in genotyped long QT syndrome. | Nemec J | Pacing and clinical electrophysiology : PACE | 2003 | PMID: 12877697 |
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Text-mined citations for rs199472754 ...
HelpRecord last updated Feb 14, 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.