ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.565G>A (p.Gly189Arg)
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.565G>A (p.Gly189Arg)
Variation ID: 3114 Accession: VCV000003114.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570715 (GRCh38) [ NCBI UCSC ] 11: 2591945 (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 Apr 4, 2013 Feb 14, 2024 Oct 28, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.565G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Gly189Arg missense NM_001406836.1:c.565G>A NP_001393765.1:p.Gly189Arg missense NM_001406837.1:c.295G>A NP_001393766.1:p.Gly99Arg missense NM_181798.2:c.184G>A NP_861463.1:p.Gly62Arg missense NR_040711.2:n.458G>A NC_000011.10:g.2570715G>A NC_000011.9:g.2591945G>A NG_008935.1:g.130725G>A LRG_287:g.130725G>A LRG_287t1:c.565G>A LRG_287p1:p.Gly189Arg LRG_287t2:c.184G>A LRG_287p2:p.Gly62Arg P51787:p.Gly189Arg - Protein change
- G189R, G62R, G99R
- Other names
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- Canonical SPDI
- NC_000011.10:2570714: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.
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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 |
1648 | 2513 |
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
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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) |
no assertion criteria provided
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Jan 1, 1999 | RCV000003261.3 | |
not provided (1) |
no classification provided
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- | RCV000057702.4 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jun 18, 2020 | RCV000223880.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 28, 2020 | RCV001383882.5 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Likely pathogenic
(Jun 18, 2020)
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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: SCV000516040.3
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Identified in a patient with LQTS referred for genetic testing at GeneDx and observed in association with LQTS in the published literature (Wang et al., … (more)
Identified in a patient with LQTS referred for genetic testing at GeneDx and observed in association with LQTS in the published literature (Wang et al., 1996; Wang et al., 1999; Jongbloed et al., 1999; Moss et al., 2007; Goldenberg et al., 2011; Nannenberg et al., 2012; Barsheshet et al., 2012); Published functional studies suggest damaging effect with loss of function but little dominant-negative impact (Wang et al., 1999) and reduction in normalized current (Barasheshet et al., 2012); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22456477, 8528244, 10220144, 22373669, 27807201, 17470695, 21185501, 10376919) (less)
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Pathogenic
(Oct 28, 2020)
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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: SCV001583199.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect KCNQ1 protein function (PMID: 10376919, 22456477). This variant … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect KCNQ1 protein function (PMID: 10376919, 22456477). This variant has been observed to segregate with long QT syndrome in families and has been observed in individuals affected with this condition (PMID: 8528244, 22373669, 22456477, 10376919). This variant is also known as G60R in the literature. ClinVar contains an entry for this variant (Variation ID: 3114). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 189 of the KCNQ1 protein (p.Gly189Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. (less)
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Pathogenic
(Jan 01, 1999)
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no assertion criteria provided
Method: literature only
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LONG QT SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023419.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a family in which 3 members had LQT1 (192500), Wang et al. (1996) demonstrated a GGG (gly) to AGG (arg) transition in codon 189 … (more)
In a family in which 3 members had LQT1 (192500), Wang et al. (1996) demonstrated a GGG (gly) to AGG (arg) transition in codon 189 of the KVLQT1 gene. Jongbloed et al. (1999) identified this mutation in 2 families with LQT1. (This variant used to be known as GLY60ARG and GLY94ARG.) (less)
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Pathogenic
(Jan 27, 2014)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280157.1
First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Gly189Arg Based on the information reviewed below, we classify it as very likely disease causing. This variant has previously been reported in at least 3 unrelated individuals with LQTS. There is very strong published segregation data. Jongbloed et al. (1999) identified this variant in 2 Dutch families with LQT1. It segregated with disease in 17 affected members of one family (2 of them asymptomatic), and 3 affected members of the other (one of them asymptomatic). Wang et al. (1996) had previously reported that it segregated with disease in 3 affected siblings in a family with LQTS. Nannenberg et al. (2012) reported it in a Dutch family with LQT1 in which they traced the disease back centuries, although it is not clear if this family was included in Jongbloed et al. (According to OMIM, this variant used to be known as GLY60ARG, by Wang et al., and GLY94ARG.) Another variant at this same codon, Gly189Glu, has been reported in association with LQTS (HGMD cites Moss et al. 2007, Giudicessi et al. 2012, and another). This is a non-conservative amino acid change, resulting in the replacement of a nonpolar glycine with a positively-charged arginine with a much bulkier side-chain. Glycine at this location is highly conserved across vertebrate species (it is an alanine in a species of falcon). Variation at nearby residues has been associated with LQTS, which may support the functional importance of this region of the protein: G179S, K183R, K183M, Y184H, Y184S, G186R, G186S, L187P, R190W, R190L, R190Q, L191P, R192C, R192H, R192P, F193L, A194P, R195W, I198V, S199A (HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.0. In vitro functional studies show that it results in a loss of KCNQ1 channel function (Wang et al. 1999, Barsheshet et al 2012). This residue is in the cytoplasmic S2-S3 linker. It is not entirely possible to tell from the location within the KCNQ1 protein if a variant causes disease. However, when Kapa et al. (2009) compared 388 “clinically definite” LQTS probands to ~1300 healthy controls, they found that LQTS cases were much more likely to have missense variants in the C-terminal cytoplasmic region of the KCNQ1 protein (amino acid residues 349-676), the pore region, transmembrane region, or linker region (residues 122-348)—rather than in the N-terminal domain (residues 1-121). Variants in the transmembrane-linker-pore domain of the protein were 24x more frequent in LQTS cases than in controls. In total the variant has not been seen in over 60,000 published controls and individuals from publicly available population datasets. The variant was not observed in published controls: 55 individuals (Jongbloed et al. 1999; didn’t check the other references). As of 6/5/2015, there is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. Our patient’s ancestry is Caucasian. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. This variant was not found in 1000 Genomes (http://browser.1000genomes.org/index.htm). The variant is not present in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. (less)
Number of individuals with the variant: 4
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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: SCV000089221.3
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:8528244;PMID:10220144;PMID:17470695;PMID:10220144). 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:8528244;PMID:10220144;PMID:17470695;PMID:10220144). 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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Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome. | Barsheshet A | Circulation | 2012 | PMID: 22456477 |
Mortality of inherited arrhythmia syndromes: insight into their natural history. | Nannenberg EA | Circulation. Cardiovascular genetics | 2012 | PMID: 22373669 |
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 |
Functional effects of mutations in KvLQT1 that cause long QT syndrome. | Wang Z | Journal of cardiovascular electrophysiology | 1999 | PMID: 10376919 |
Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. | Jongbloed RJ | Human mutation | 1999 | PMID: 10220144 |
Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. | Wang Q | Nature genetics | 1996 | PMID: 8528244 |
Text-mined citations for rs104894252 ...
HelpRecord last updated Feb 20, 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.