ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.574C>T (p.Arg192Cys)
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.574C>T (p.Arg192Cys)
Variation ID: 578178 Accession: VCV000578178.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570724 (GRCh38) [ NCBI UCSC ] 11: 2591954 (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 10, 2018 Feb 28, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.574C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg192Cys missense NM_001406836.1:c.574C>T NP_001393765.1:p.Arg192Cys missense NM_001406837.1:c.304C>T NP_001393766.1:p.Arg102Cys missense NM_181798.2:c.193C>T NP_861463.1:p.Arg65Cys missense NR_040711.2:n.467C>T NC_000011.10:g.2570724C>T NC_000011.9:g.2591954C>T NG_008935.1:g.130734C>T LRG_287:g.130734C>T LRG_287t1:c.574C>T LRG_287p1:p.Arg192Cys LRG_287t2:c.193C>T LRG_287p2:p.Arg65Cys - Protein change
- R65C, R192C, R102C
- Other names
- p.Arg192Cys
- Canonical SPDI
- NC_000011.10:2570723: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.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
- Links
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
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 | 2506 |
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
Help
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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Uncertain significance (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV000701111.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 12, 2018 | RCV000825352.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 24, 2023 | RCV001841870.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 16, 2021 | RCV002343532.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 22, 2021 | RCV002493227.8 |
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
(Sep 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966647.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg192Cys variant in KCNQ1 has been reported in 1 heterozygous individual and 2 compound heterozygous individuals … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg192Cys variant in KCNQ1 has been reported in 1 heterozygous individual and 2 compound heterozygous individuals with long QT syndrome (LQTS), and one case with sudden death (Gao 2012, Lieve 2013, McLeod 2017, Suktitipat 2017). None of the compound heterozygous individuals had hearing loss. This variant has been identified in 0.05% (9/18834) of East Asian chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org). Computational prediction tools and cons ervation analysis suggest that the p.Arg192Cys variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, while there is some suspicion for a pathogenic role, the clinical signif icance of the p.Arg192Cys variant is uncertain. ACMG/AMP criteria applied: PS4_S upporting, PM2_Supporting, PP3. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Dec 16, 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: SCV002650707.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R192C variant (also known as c.574C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide … (more)
The p.R192C variant (also known as c.574C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 574. The arginine at codon 192 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in conjunction with a KCNE1 variant and in trans with KCNQ1 c.1032G>A in an individual with Romano Ward syndrome; this variant was also identified in the proband's unaffected mother (Gao Y et al. J Cardiovasc Dis Res, 2012 Apr;3:67-75). This variant was identified in a long QT syndrome (LQTS) cohort (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61), in a sudden death victim in conjunction with a variant in DSP (Suktitipat B et al. PLoS ONE, 2017 Jul;12:e0180056), and in an individual with LQTS in conjunction with KCNQ1 p.G179S (McLeod KA et al. Cardiol Young, 2017 Sep;27:1271-1279). Function studies in Xenopus oocytes demonstrated an increased current, whereas studies in CHO cells demonstrated a reduced current (Eckey K et al. J. Biol. Chem., 2014 Aug;289:22749-58; Vanoye CG et al. Circ Genom Precis Med, 2018 11;11:e002345). 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)
Number of individuals with the variant: 1
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Uncertain significance
(Nov 22, 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: SCV002780372.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Apr 24, 2023)
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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: SCV001734978.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 192 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with cysteine at codon 192 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that the current of the mutant channel was significantly decreased upon PIP2 injection, indicating an impaired functional interaction with PIP2 (PMID: 24947509). This variant has been reported in individuals affected with or suspected of having long QT syndrome, epilepsy, arrhythmia, sudden unexpected death syndrome, or other diseases (PMID: 22629021, 23631430, 28704380, 28606196, 31696929). This variant has been identified in 11/280628 chromosomes (10/19916 East Asian 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
(Jan 22, 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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Invitae
Accession: SCV000829894.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 192 of the KCNQ1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 192 of the KCNQ1 protein (p.Arg192Cys). This variant is present in population databases (rs775059928, gnomAD 0.05%). This missense change has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 22629021, 23631430, 28606196, 28704380). ClinVar contains an entry for this variant (Variation ID: 578178). 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, 30571187). 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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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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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 |
High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance. | Vanoye CG | Circulation. Genomic and precision medicine | 2018 | PMID: 30571187 |
Molecular investigation by whole exome sequencing revealed a high proportion of pathogenic variants among Thai victims of sudden unexpected death syndrome. | Suktitipat B | PloS one | 2017 | PMID: 28704380 |
Prescribing an automated external defibrillator for children at increased risk of sudden arrhythmic death. | McLeod KA | Cardiology in the young | 2017 | PMID: 28606196 |
Novel Kv7.1-phosphatidylinositol 4,5-bisphosphate interaction sites uncovered by charge neutralization scanning. | Eckey K | The Journal of biological chemistry | 2014 | PMID: 24947509 |
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 |
Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome. | Gao Y | Journal of cardiovascular disease research | 2012 | PMID: 22629021 |
Text-mined citations for rs775059928 ...
HelpRecord last updated Mar 23, 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.