ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.583C>T (p.Arg195Trp)
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.583C>T (p.Arg195Trp)
Variation ID: 67087 Accession: VCV000067087.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570733 (GRCh38) [ NCBI UCSC ] 11: 2591963 (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 11, 2015 Apr 15, 2024 Feb 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.583C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg195Trp missense NM_001406836.1:c.583C>T NP_001393765.1:p.Arg195Trp missense NM_001406837.1:c.313C>T NP_001393766.1:p.Arg105Trp missense NM_181798.2:c.202C>T NP_861463.1:p.Arg68Trp missense NR_040711.2:n.476C>T NC_000011.10:g.2570733C>T NC_000011.9:g.2591963C>T NG_008935.1:g.130743C>T LRG_287:g.130743C>T LRG_287t1:c.583C>T LRG_287p1:p.Arg195Trp LRG_287t2:c.202C>T LRG_287p2:p.Arg68Trp P51787:p.Arg195Trp - Protein change
- R195W, R68W, R105W
- Other names
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- Canonical SPDI
- NC_000011.10:2570732:C:T
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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.
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
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
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 | 2502 |
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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not provided (1) |
no classification provided
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- | RCV000057713.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 14, 2023 | RCV000148554.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 19, 2022 | RCV001841687.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 23, 2021 | RCV002483094.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 2, 2023 | RCV003162439.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 15, 2024 | RCV003993784.1 |
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
(Jun 01, 2014)
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criteria provided, single submitter
Method: research
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Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190267.2 First in ClinVar: Dec 06, 2014 Last updated: Oct 11, 2015 |
Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
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Uncertain significance
(Dec 23, 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: SCV002783226.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Nov 14, 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: SCV000254339.5
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 195 of the KCNQ1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 195 of the KCNQ1 protein (p.Arg195Trp). This variant is present in population databases (rs150172393, gnomAD 0.006%). This missense change has been observed in individual(s) with lone atrial fibrilliation and/or long QT syndrome (PMID: 19716085, 25786344, 35703482). ClinVar contains an entry for this variant (Variation ID: 67087). 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%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 24947509, 25786344, 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
(Dec 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001346732.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 195 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with tryptophan at codon 195 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant increases channel current while has no effect on the subcellular localization of the channel protein (PMID: 25786344). This variant has been reported in an individual affected with long QT syndrome (PMID: 35703482) and in two individuals referred for long QT syndrome testing (PMID: 19716085). It has also been reported in an individual affected with early-onset lone atrial fibrillation (PMID: 24144883, 25786344). This variant has been identified in 8/280548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Feb 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813510.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: KCNQ1 c.583C>T (p.Arg195Trp) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five … (more)
Variant summary: KCNQ1 c.583C>T (p.Arg195Trp) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249190 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.583C>T has been reported in the literature in individuals affected with long-QT syndrome or atrial fibrillation (Kapplinger_2009, Olesen_2013, Steffensen_2015, Diebold_2020, Saat_2022). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least two publications report experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Steffensen_2015, Huang_2021). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 32048431, 33600800, 19716085, 24190995, 24144883, 35703482, 25786344). ClinVar contains an entry for this variant (Variation ID: 67087). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Mar 02, 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: SCV003900425.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The p.R195W variant (also known as c.583C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide … (more)
The p.R195W variant (also known as c.583C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 583. The arginine at codon 195 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a long QT syndrome clinical genetic testing cohort, an early-onset atrial fibrillation cohort, and an exome cohort, often with limited clinical detail (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Olesen MS et al. Heart Rhythm, 2014 Feb;11:246-51; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). In vitro studies have suggested that this mutant enhances the channel activity and reduces protein cell-surface expression; however, additional evidence is needed to confirm these findings. (Steffensen AB et al. J. Cardiovasc. Electrophysiol., 2015 Jul;26:715-23; Huang H et al. J Biol Chem. 2021 Feb;296:100423). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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: SCV000089232.3
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:19716085). 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:19716085). 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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Molecular Approach of Hereditary Arrhythmias, Long QT Syndrome, and Arrhythmogenic Right Ventricular Cardiomyopathy. | Saat H | Anatolian journal of cardiology | 2022 | PMID: 35703482 |
Predicting the functional impact of KCNQ1 variants with artificial neural networks. | Phul S | PLoS computational biology | 2022 | PMID: 35442947 |
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 |
IKs Gain- and Loss-of-Function in Early-Onset Lone Atrial Fibrillation. | Steffensen AB | Journal of cardiovascular electrophysiology | 2015 | PMID: 25786344 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Novel Kv7.1-phosphatidylinositol 4,5-bisphosphate interaction sites uncovered by charge neutralization scanning. | Eckey K | The Journal of biological chemistry | 2014 | PMID: 24947509 |
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 |
Intracellular ATP binding is required to activate the slowly activating K+ channel I(Ks). | Li Y | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 24190995 |
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 |
Text-mined citations for rs150172393 ...
HelpRecord last updated Apr 15, 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.