ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.965C>G (p.Thr322Arg)
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.965C>G (p.Thr322Arg)
Variation ID: 200830 Accession: VCV000200830.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2583478 (GRCh38) [ NCBI UCSC ] 11: 2604708 (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 May 29, 2016 May 1, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.965C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Thr322Arg missense NM_001406836.1:c.965C>G NP_001393765.1:p.Thr322Arg missense NM_001406837.1:c.695C>G NP_001393766.1:p.Thr232Arg missense NM_001406838.1:c.521C>G NP_001393767.1:p.Thr174Arg missense NM_181798.2:c.584C>G NP_861463.1:p.Thr195Arg missense NR_040711.2:n.858C>G NC_000011.10:g.2583478C>G NC_000011.9:g.2604708C>G NG_008935.1:g.143488C>G LRG_287:g.143488C>G LRG_287t1:c.965C>G LRG_287p1:p.Thr322Arg LRG_287t2:c.584C>G LRG_287p2:p.Thr195Arg - Protein change
- T195R, T322R, T232R, T174R
- Other names
- p.T322R:ACG>AGG
- Canonical SPDI
- NC_000011.10:2583477:C: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
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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
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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 |
1720 | 2663 |
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
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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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Pathogenic (1) |
criteria provided, single submitter
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May 17, 2013 | RCV000182148.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2024 | RCV001852304.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 14, 2021 | RCV002372112.2 |
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
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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
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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
(May 17, 2013)
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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: SCV000234451.10
First in ClinVar: Jul 05, 2015 Last updated: May 29, 2016 |
Comment:
p.Thr322Arg (ACG>AGG): c.965 C>G in exon 7 of the KCNQ1 gene (NM_000218.2). While the Thr322Arg mutation in the KCNQ1 gene has not been reported to … (more)
p.Thr322Arg (ACG>AGG): c.965 C>G in exon 7 of the KCNQ1 gene (NM_000218.2). While the Thr322Arg mutation in the KCNQ1 gene has not been reported to our knowledge, mutations affecting this same residue (Thr322Ala, Thr322Met, Thr322Lys) have been reported in association with LQTS (Choi G et al., 2004; Napolitano C et al., 2005; Hedley P et al., 2009). Additionally, mutations in nearby residues (Pro320Ser, Pro320Ala, Pro320His, Gly325Trp, Gly325Arg, Gly325Glu) have been reported in association with LQTS, supporting the functional importance of this residue and this region of the protein. Thr322Arg results in a semi-conservative amino acid substitution of a neutral, polar Threonine with a positively charged Arginine at a position that is conserved across species. Furthermore, Thr322Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Thr322Arg in the KCNQ1 gene has been observed in other unrelated individuals at GeneDx. The variant is found in LQT panel(s). (less)
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Likely pathogenic
(Jan 01, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002220851.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 322 of the KCNQ1 protein (p.Thr322Arg). … (more)
This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 322 of the KCNQ1 protein (p.Thr322Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 200830). 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 with a positive predictive value of 95%. 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, 22949429, 23092362). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Sep 14, 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: SCV002689121.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.T322R variant (also known as c.965C>G), located in coding exon 7 of the KCNQ1 gene, results from a C to G substitution at nucleotide … (more)
The p.T322R variant (also known as c.965C>G), located in coding exon 7 of the KCNQ1 gene, results from a C to G substitution at nucleotide position 965. The threonine at codon 322 is replaced by arginine, 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 an individual with a clinical diagnosis of long QT syndrome (Ambry Internal Data). Another alteration at the same codon, p.T322A (c.964A>G), has been reported in multiple individuals with a clinical diagnosis of long QT syndrome (Nemec J et al. Pacing Clin Electrophysiol, 2003 Aug;26:1660-7; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Westphal DS et al. Mol Genet Genomic Med, 2020 09;8:e1300), and in vitro studies suggest that the p.T322A alteration results in abnormal protein function (Burgess DE et al. Biochemistry, 2012 Nov;51:9076-85). Evidence from structural analysis predicts this alteration to destabilize a known protein-protein binding region (Long SB et al. Nature 2007;450(7168):376-82; Xu Yet al. Biophys. J. 2013;105(11):2461-73). 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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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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Building KCNQ1/KCNE1 channel models and probing their interactions by molecular-dynamics simulations. | Xu Y | Biophysical journal | 2013 | PMID: 24314077 |
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 |
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 |
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 |
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. | Long SB | Nature | 2007 | PMID: 18004376 |
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 |
Text-mined citations for rs199472755 ...
HelpRecord last updated Sep 29, 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.