ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.683+5G>A
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.
Pathogenic(4); Likely pathogenic(5); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000218.3(KCNQ1):c.683+5G>A
Variation ID: 53084 Accession: VCV000053084.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2571408 (GRCh38) [ NCBI UCSC ] 11: 2592638 (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 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.683+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001406836.1:c.683+5G>A intron variant NM_001406837.1:c.413+5G>A intron variant NM_001406838.1:c.478-12027G>A intron variant NM_181798.2:c.302+5G>A intron variant NC_000011.10:g.2571408G>A NC_000011.9:g.2592638G>A NG_008935.1:g.131418G>A LRG_287:g.131418G>A LRG_287t1:c.683+5G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:2571407:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- sequence_variant_affecting_splicing Sequence Ontology [SO:1000071]
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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), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00001
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 |
1703 | 2599 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Oct 20, 2022 | RCV000182098.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 10, 2020 | RCV001255476.9 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 20, 2024 | RCV001389794.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 20, 2023 | RCV001841650.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2023 | RCV002362678.10 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 8, 2023 | RCV002267608.11 |
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. |
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Pathogenic
(Jun 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: unknown
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002549818.1
First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022 |
Comment:
_x000D_ Criteria applied: PS3, PS4, PP3
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Likely pathogenic
(Oct 05, 2022)
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criteria provided, single submitter
Method: research, in vitro
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Long QT syndrome 1
Affected status: not applicable, unknown
Allele origin:
unknown,
not applicable
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Roden Lab, Vanderbilt University Medical Center
Accession: SCV002588741.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
The KCNQ1 c.683+5G>A variant was observed in 3 cases of LQTS and was observed rarely in population databases (PMID: 32893267). A minigene assay provided experimental … (more)
The KCNQ1 c.683+5G>A variant was observed in 3 cases of LQTS and was observed rarely in population databases (PMID: 32893267). A minigene assay provided experimental support for this prediction. Collectively, this evidence allows the classification of this variant as Likely Pathogenic. (less)
Observation 1: Observation 2:
Method: Minigene Assay
Result:
A HEK293T minigene assay showed multiple pseudoexon inclusions in the variant but not WT plasmid.
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Likely pathogenic
(Oct 20, 2022)
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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: SCV000234401.15
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Other splice site variants, including variants at the same splice donor site (c.683+2 T>G, c.683+1G>A) have been reported in HGMD in association with KCNQ1-related disorders … (more)
Other splice site variants, including variants at the same splice donor site (c.683+2 T>G, c.683+1G>A) have been reported in HGMD in association with KCNQ1-related disorders (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28438721, 23631430, 17470695, 19841300, 7446532, 25525159, 27917693, 32383558, 31737537, 36197721, 26318259, 22456477, 34135346, 34319147, 29740400, 29622001, 26669661, 19862833, 36232963) (less)
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Pathogenic
(Sep 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004183540.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Jan 20, 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: SCV001591272.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 4 of the KCNQ1 gene. It does not directly change the encoded amino acid sequence of the KCNQ1 protein. … (more)
This sequence change falls in intron 4 of the KCNQ1 gene. It does not directly change the encoded amino acid sequence of the KCNQ1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs397508122, gnomAD 0.003%). This variant has been observed in individual(s) with long QT syndrome and Jervell and Lange-Nielsen syndrome (PMID: 17470695, 19841300, 23631430, 27917693, 28438721, 29622001). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS4+5G>A. ClinVar contains an entry for this variant (Variation ID: 53084). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Aug 10, 2020)
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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: SCV001431894.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment:
Variant summary: KCNQ1 c.683+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: KCNQ1 c.683+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 248582 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.683+5G>A has been reported in the literature in individuals affected with LQTS and Jervell and Lange-Nielsen Syndrome (Moss_2007, Kapa_2009, Barsheshet_2012, Lieve_2013, Ruwald_2016, Wang_2016, Al-Hassnan_2017, Koponen_2018, Huttunen_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. In addition, co-occurrence with another pathogenic variant has been reported (KCNQ1 c.1484_1485delCT, p.L496AfsX19, Wang_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes
Accession: SCV004024170.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
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Likely pathogenic
(Apr 20, 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: SCV001340315.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G>A nucleotide substitution at the +5 position of intron 4 of the KCNQ1 gene. In vitro mini-gene splice assays have shown … (more)
This variant causes a G>A nucleotide substitution at the +5 position of intron 4 of the KCNQ1 gene. In vitro mini-gene splice assays have shown that this variant causes a complete abrogation of WT splicing, while skipping exon 4 or introducing a pseudoexon in the majority of transcripts (PMID: 36197721, doi:10.4081/cardiogenetics.2012.e6). This variant has been reported in at lest six individuals affected with long QT syndrome (PMID: 19841300, 23631430, 26318259, 26669661, 28438721, 29740400). This variant has also been reported in compound heterozygosity with a pathogenic variant in individuals affected with severe phenotype (doi:10.4081/cardiogenetics.2012.e6) or with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 27917693). This variant has also been identified in 4/271744 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely Pathogenic
(Jul 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004826263.1
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)
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Comment:
This variant causes a G>A nucleotide substitution at the +5 position of intron 4 of the KCNQ1 gene. In vitro mini-gene splice assays have shown … (more)
This variant causes a G>A nucleotide substitution at the +5 position of intron 4 of the KCNQ1 gene. In vitro mini-gene splice assays have shown that this variant causes a complete abrogation of WT splicing, while skipping exon 4 or introducing a pseudoexon in the majority of transcripts (PMID: 36197721, doi:10.4081/cardiogenetics.2012.e6). This variant has been reported in at lest six individuals affected with long QT syndrome (PMID: 19841300, 23631430, 26318259, 26669661, 28438721, 29740400). This variant has also been reported in compound heterozygosity with a pathogenic variant in individuals affected with severe phenotype (doi:10.4081/cardiogenetics.2012.e6) or with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 27917693). This variant has also been identified in 4/271744 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 2
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Likely pathogenic
(Feb 08, 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: SCV002664970.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.683+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 4 in the KCNQ1 gene. This alteration has been … (more)
The c.683+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 4 in the KCNQ1 gene. This alteration has been detected in individuals with long QT syndrome (LQTS) and in compound heterozygotes with Jervell and Lange-Nielsen syndrome (JLNS), as well as in some asymptomatic carrier parents (Moss AJ et al. Circulation, 2007 May;115:2481-9; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Crehalet H et al. Cardiogen., 2012;2:26-31; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Wang C et al. Acta Otolaryngol., 2017 May;137:522-528; Al-Hassnan ZN et al. Heart Rhythm, 2017 Aug;14:1191-1199). RNA splicing studies demonstrated this alteration leads to skipping of exon 4 (Crehalet H et al. Cardiogen., 2012;2:26-31). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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sequence_variant_affecting_splicing
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Roden Lab, Vanderbilt University Medical Center
Accession: SCV002588741.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Functional Assays Reclassify Suspected Splice-Altering Variants of Uncertain Significance in Mendelian Channelopathies. | O'Neill MJ | Circulation. Genomic and precision medicine | 2022 | PMID: 36197721 |
The Role of KCNQ1 Mutations and Maternal Beta Blocker Use During Pregnancy in the Growth of Children With Long QT Syndrome. | Huttunen H | Frontiers in endocrinology | 2018 | PMID: 29740400 |
Clinical and molecular genetic risk determinants in adult long QT syndrome type 1 and 2 patients : Koponen et al. Follow-up of adult LQTS patients. | Koponen M | BMC medical genetics | 2018 | PMID: 29622001 |
Clinical profile and mutation spectrum of long QT syndrome in Saudi Arabia: The impact of consanguinity. | Al-Hassnan ZN | Heart rhythm | 2017 | PMID: 28438721 |
Identification of KCNQ1 compound heterozygous mutations in three Chinese families with Jervell and Lange-Nielsen Syndrome. | Wang C | Acta oto-laryngologica | 2017 | PMID: 27917693 |
Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction. | Itoh H | European journal of human genetics : EJHG | 2016 | PMID: 26669661 |
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 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
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 |
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 |
The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
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 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs397508122 ...
HelpRecord last updated Jun 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.