ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.1394-1G>T
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.1394-1G>T
Variation ID: 200847 Accession: VCV000200847.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2683190 (GRCh37) [ NCBI UCSC ] 11: 2661960 (GRCh38) [ 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 Oct 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.1394-1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001406836.1:c.1298-1G>T splice acceptor NM_001406837.1:c.1124-1G>T splice acceptor NM_001406838.1:c.854-1G>T splice acceptor NM_181798.2:c.1013-1G>T splice acceptor NR_002728.4:n.38035C>A NC_000011.10:g.2661960G>T NC_000011.9:g.2683190G>T NG_008935.1:g.221970G>T NG_016178.2:g.43039C>A LRG_1052:g.43039C>A LRG_1052t1:n.38039C>A LRG_287:g.221970G>T LRG_287t1:c.1394-1G>T - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:2661959:G: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), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 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 |
1702 | 2589 | |
KCNQ1OT1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1 | 653 |
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 (2) |
criteria provided, single submitter
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Jul 24, 2023 | RCV000182190.19 | |
Pathogenic (1) |
criteria provided, single submitter
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May 12, 2021 | RCV000620890.11 | |
Pathogenic (1) |
criteria provided, single submitter
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May 30, 2023 | RCV001842872.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 10, 2023 | RCV000631611.19 |
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
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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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Pathogenic
(Oct 10, 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: SCV000752693.8
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 10 of the KCNQ1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 10 of the KCNQ1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This variant is present in population databases (rs775537394, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with long QT syndrome (PMID: 17905336, 23631430, 26318259; Invitae). This variant is also known as IVS10-1G>T. ClinVar contains an entry for this variant (Variation ID: 200847). 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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Pathogenic
(May 12, 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: SCV000738035.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The c.1394-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 11 of the KCNQ1 gene. This alteration … (more)
The c.1394-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 11 of the KCNQ1 gene. This alteration (also referred to as IVS10-1G>T) has been detected in a subject with long QT syndrome (LQTS) who also carried a second frameshift alteration in KCNH2 (Chung SK et al. Heart Rhythm, 2007 Oct;4:1306-14). This alteration was also reported in additional LQTS cohorts; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Ruwald MH et al. Heart Rhythm. 2016 Jan;13(1):122-31). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Sep 01, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919557.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The KCNQ1 c.1394-1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. … (more)
Variant summary: The KCNQ1 c.1394-1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was found in the control population dataset of ExAC in 1/121208 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0000833). This variant was reported in multiple patients with LQTS in the literature (Chung_2007, Lieve_2013, Ruwald_2016) and was stated as segregating with LQTS in a family (Stanford Center for Inherited Cardiovascular Disease). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 24, 2023)
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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: SCV000234493.17
First in ClinVar: Jul 05, 2015 Last updated: Jul 29, 2023 |
Comment:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts … (more)
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in an individual diagnosed with severe LQTS who also harbored a frameshift variant in the KCNH2 gene (Chung et al., 2007); This variant is associated with the following publications: (PMID: 25525159, 19862833, 9323054, 23631430, 26318259, 34135346, 34319147, 17905336, 33087929) (less)
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Pathogenic
(May 30, 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: SCV002052724.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to T nucleotide substitution at the -1 position of intron 10 (also known as IVS10-1G>T) of the KCNQ1 gene. Splice … (more)
This variant causes a G to T nucleotide substitution at the -1 position of intron 10 (also known as IVS10-1G>T) of the KCNQ1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been observed in multiple individuals affected with or suspected of having long QT syndrome (PMID: 17905336, 23631430, 26318259, ClinVar SCV000280145.1, communication with external laboratories: SCV000752693.7, SCV000234493.16, SCV000738035.4). It has been reported that this variant segregates with disease in at least one of the families (communication with an external laboratory ClinVar SCV000234493.16). This variant has also been reported in a healthy individual aged 70 years or older without a history of coronary heart disease (PMID: 34135346). This variant has been identified in 1/251392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Oct 31, 2013)
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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: SCV000280145.1
First in ClinVar: May 29, 2016 Last updated: May 29, 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 IVS10-1G>T (c.1394-1G>T) Based on the data reviewed below, we consider it likely disease-causing. This variant has been seen in at least one published case in the literature. We have also found it segregating with LQTS in one family at our center. Chung et al. 2007 identified this splice variant in addition to a frameshift insertion in KCNH2 in a patient with “severe LQTS”. In terms of clinical details, this patient was Caucasian, had a personal history of syncope and a family history of SCD in a first degree relative, and had a QTc of 520 ms. Her diagnosis was described as “LQT1/LQT2”). It was absent from 50 control individuals in this study. This variant is very likely to disrupt normal splicing, as it changes the last base of intron 10 from a G to a T thus destroying the canonical G nucleotide of the splice acceptor site. There are several splice, nonsense and frameshift variants that have been associated with LQTS in the literature, including nearby splicing variants also in the c-terminus (922-1G>C; 1251+2T>C; 1514+1G>A). In total, this variant has not been seen in approximately 6,650 publicly available population and laboratory controls (including ~6,500 individuals of African American and European ancestry from NHLBI ESP dataset; 100 Caucasian individuals from GeneDx; and 50 individuals from Chung et al. 2007). There is a variant involving this same splice acceptor site seen in 6 individuals in ESP, however it is at the -8 position (thus unlikely to have the same effect as changing the canonical splice acceptor site). This variant has also not been observed in the 1000Genomes dataset or dbSNP as of October 31, 2013. This variant is currently present in HGMD and LOVD as a disease-causing mutation on the basis of the Chung et al. 2007 variant. (less)
Number of individuals with the variant: 3
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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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Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent. | Lacaze P | NPJ genomic medicine | 2021 | PMID: 34135346 |
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 |
The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
Long QT and Brugada syndrome gene mutations in New Zealand. | Chung SK | Heart rhythm | 2007 | PMID: 17905336 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. | Shalaby FY | Circulation | 1997 | PMID: 9323054 |
High-level language implementation of bit map inverted files. | Ragan DP | Computers and biomedical research, an international journal | 1978 | PMID: 738035 |
Action of oral contraceptive drugs on protein metabolism in rats. | Khayyal MT | The Journal of the Egyptian Medical Association | 1977 | PMID: 752693 |
Antiviral activities of 4'-(9-acridinylamino)-methanesulfon-M-aniside (SN11841). | Byrd DM | Annals of the New York Academy of Sciences | 1977 | PMID: 280145 |
Traumatic neuropathy of the intermediate dorsal cutaneous nerve (Lemont's nerve): A case report. | Bergman MA | Journal of the American Podiatry Association | 1975 | PMID: 234493 |
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Text-mined citations for rs775537394 ...
HelpRecord last updated May 08, 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.