ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.1553G>A (p.Arg518Gln)
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
-
NM_000218.3(KCNQ1):c.1553G>A (p.Arg518Gln)
Variation ID: 67036 Accession: VCV000067036.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.5 11: 2768882 (GRCh38) [ NCBI UCSC ] 11: 2790112 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 6, 2014 Sep 16, 2024 Jul 10, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000218.3:c.1553G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg518Gln missense NM_001406836.1:c.1457G>A NP_001393765.1:p.Arg486Gln missense NM_001406837.1:c.1283G>A NP_001393766.1:p.Arg428Gln missense NM_001406838.1:c.1013G>A NP_001393767.1:p.Arg338Gln missense NM_181798.2:c.1172G>A NP_861463.1:p.Arg391Gln missense NR_040711.2:n.1446G>A NC_000011.10:g.2768882G>A NC_000011.9:g.2790112G>A NG_008935.1:g.328892G>A LRG_287:g.328892G>A LRG_287t1:c.1553G>A LRG_287p1:p.Arg518Gln LRG_287t2:c.1172G>A LRG_287p2:p.Arg391Gln P51787:p.Arg518Gln - Protein change
- R518Q, R391Q, R338Q, R428Q, R486Q
- Other names
- -
- Canonical SPDI
- NC_000011.10:2768881:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
KCNQ1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1718 | 2652 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
not provided (1) |
no classification provided
|
- | RCV000057593.11 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000148557.16 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jul 10, 2024 | RCV000505803.15 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 24, 2022 | RCV001824592.9 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Dec 6, 2023 | RCV001841668.11 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Sep 1, 2021 | RCV002483092.8 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Dec 1, 2022 | RCV003162436.9 |
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
Help
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Jan 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074417.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: KCNQ1 c.1553G>A (p.Arg518Gln) results in a conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal domain (IPR013821) of the … (more)
Variant summary: KCNQ1 c.1553G>A (p.Arg518Gln) results in a conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal domain (IPR013821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1553G>A has been reported in the literature in individuals affected with Long QT syndrome, sudden infant death, epilepsy and hypertrophic cardiomyopathy (examples: Kapplinger_2009, Costa_2012, Lieve_2013, Ghouse_2015, Ruwald_2016, Tester_2018, Li_2019, Dai_2021). In addition, the variant was found to co-occur with a pathogenic RYR2 variant (c.527G>T, p.Arg176Leu) in a female affected with cardiac arrest and her brother exhibiting catecholaminergic polymorphic ventricular tachycardia (CPVT) phenotype. Their mother who was also affected with cardiac arrest was found to only carry the RYR2 variant, as were multiple symptomatic members from the maternal side of the family. The authors concluded that the RYR2 variant was predisposing to low penetrant CPVT in this family (Tung_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function. Slaats_2015 demonstrated that KCNQ1-p.R518Q variant could rescue ciliogenecis defect to the same levels as wild-type. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Sep 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002790001.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001540109.4
First in ClinVar: Mar 22, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 518 of the KCNQ1 protein (p.Arg518Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 518 of the KCNQ1 protein (p.Arg518Gln). This variant is present in population databases (rs145974930, gnomAD 0.005%). This missense change has been observed in individual(s) with sudden infant death syndrome and in individuals with QT intervals in the normal range (PMID: 26159999, 29544605). ClinVar contains an entry for this variant (Variation ID: 67036). 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 not expected to disrupt KCNQ1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect KCNQ1 function (PMID: 26546361). This variant disrupts the p.Arg518 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16414944, 21511995, 24363352; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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)
|
|
Uncertain significance
(Dec 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003900362.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
The c.1553G>A (p.R518Q) alteration is located in exon 12 (coding exon 12) of the KCNQ1 gene. This alteration results from a G to A substitution … (more)
The c.1553G>A (p.R518Q) alteration is located in exon 12 (coding exon 12) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 1553, causing the arginine (R) at amino acid position 518 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(Jul 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234500.12
First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024 |
Comment:
Observed in individuals with Long QT syndrome and sudden infant death syndrome in the published literature (Kapplinger et al., 2009; Ghouse et al., 2015; Tester … (more)
Observed in individuals with Long QT syndrome and sudden infant death syndrome in the published literature (Kapplinger et al., 2009; Ghouse et al., 2015; Tester et al., 2018); Published functional studies demonstrate the R518Q variant retains function and have suggested this is a benign variant (Slaats et al., 2015); 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: 22581653, 25637381, 25854863, 26159999, 32048431, 29544605, 19716085, 31994352, Rida2023[review], 26546361, 26318259, 34333030, 31696929, 38014677) (less)
|
|
Uncertain significance
(Dec 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001355492.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 518 of the KCNQ1 protein. Computational prediction tools indicate that this variant has a deleterious impact … (more)
This missense variant replaces arginine with glutamine at codon 518 of the KCNQ1 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved C-terminus region (a.a. 509-575). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant does not affect the ability of KCNQ1 protein to regulate renal ciliogenesis (PMID: 19716085, 26546361). This variant has been reported in an individual affected with sudden infant death syndrome (PMID: 29544605) and in several individuals referred for long QT syndrome genetic testing (PMID: 19716085, 26159999). Mean QTc interval of the carriers was not significantly different from that of non-carriers (PMID: 26159999). This variant has also been reported in one individual affected with cardiac arrest; however, the sibling who also carried the variant was asymptomatic (PMID: 31994352). This variant has been identified in 9/282772 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)
|
|
Uncertain Significance
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004836457.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces arginine with glutamine at codon 518 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 518 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). Functional studies have shown that this variant does not affect the ability of KCNQ1 protein to regulate renal ciliogenesis (PMID: 19716085, 26546361). This variant has been reported in an individual affected with sudden infant death syndrome (PMID: 29544605) and in several individuals referred for long QT syndrome genetic testing (PMID: 19716085, 26159999). Mean QTc interval of the carriers was not significantly different from that of non-carriers (PMID: 26159999). This variant has also been reported in one individual affected with cardiac arrest; however, the sibling who also carried the variant was asymptomatic (PMID: 31994352). This variant has been identified in 9/282772 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)
Number of individuals with the variant: 11
|
|
Uncertain significance
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190270.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089112.3
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)
|
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 |
---|---|---|---|---|
RBM20 Is a Candidate Gene for Hypertrophic Cardiomyopathy. | Dai J | The Canadian journal of cardiology | 2021 | PMID: 34333030 |
Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32893267 |
Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes. | Diebold I | Human mutation | 2020 | PMID: 32048431 |
Cardiac arrest in a mother and daughter and the identification of a novel RYR2 variant, predisposing to low penetrant catecholaminergic polymorphic ventricular tachycardia in a four-generation Canadian family. | Tung M | Molecular genetics & genomic medicine | 2020 | PMID: 31994352 |
Variant frequencies of KCNQ1, KCNH2, and SCN5A in a Chinese inherited arrhythmia cohort and other disease cohorts undergoing genetic testing. | Li X | Annals of human genetics | 2020 | PMID: 31696929 |
Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. | Tester DJ | Journal of the American College of Cardiology | 2018 | PMID: 29544605 |
Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1. | Ruwald MH | Heart rhythm | 2016 | PMID: 26318259 |
Screen-based identification and validation of four new ion channels as regulators of renal ciliogenesis. | Slaats GG | Journal of cell science | 2015 | PMID: 26546361 |
Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. | Ghouse J | European heart journal | 2015 | PMID: 26159999 |
Genetic characteristics of children and adolescents with long-QT syndrome diagnosed by school-based electrocardiographic screening programs. | Yoshinaga M | Circulation. Arrhythmia and electrophysiology | 2014 | PMID: 24363352 |
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 |
Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome. | Costa J | Heart rhythm | 2012 | PMID: 22293141 |
Detection of extra components of T wave by independent component analysis in congenital long-QT syndrome. | Horigome H | Circulation. Arrhythmia and electrophysiology | 2011 | PMID: 21511995 |
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 |
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 |
click to load more click to collapse |
Text-mined citations for rs145974930 ...
HelpRecord last updated Sep 17, 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.