ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.488del (p.Leu163fs)
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.488del (p.Leu163fs)
Variation ID: 53050 Accession: VCV000053050.16
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570638 (GRCh38) [ NCBI UCSC ] 11: 2591868 (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 Feb 20, 2024 Jun 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.488del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Leu163fs frameshift NM_000218.2:c.488delT NP_000209.2:p.Leu163Argfs frameshift NM_001406836.1:c.488delT NP_001393765.1:p.Leu163Argfs frameshift NM_001406837.1:c.218delT NP_001393766.1:p.Leu73Argfs frameshift NM_181798.2:c.107delT NP_861463.1:p.Leu36Argfs frameshift NR_040711.2:n.381delT NC_000011.10:g.2570638del NC_000011.9:g.2591868del NG_008935.1:g.130648del LRG_287:g.130648del LRG_287t1:c.488del LRG_287t2:c.107del LRG_287p2:p.Leu36fs - Protein change
- L36fs
- Other names
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- Canonical SPDI
- NC_000011.10:2570637: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.
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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 |
1696 | 2580 |
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, multiple submitters, no conflicts
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Feb 8, 2023 | RCV000182264.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 2, 2015 | RCV000217623.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 24, 2017 | RCV000709731.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 27, 2020 | RCV000618367.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 17, 2023 | RCV001215919.6 |
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
(Feb 27, 2020)
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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: SCV000737922.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The c.488delT pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of one nucleotide at position 488, causing a … (more)
The c.488delT pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of one nucleotide at position 488, causing a translational frameshift with a predicted alternate stop codon (p.L163Rfs*74). This mutation has been reported in patients referred for long QT syndrome clinical genetic testing; however, clinical details are limited (Tester DJ et al. Heart Rhythm. 2005;2:507-17; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Congenital long QT syndrome Jervell and Lange-Nielsen syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271231.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Leu163fs variant in KCNQ1 has been previously reported in at least 1 indiv idual with long QT syndrome and is absent from large population … (more)
The p.Leu163fs variant in KCNQ1 has been previously reported in at least 1 indiv idual with long QT syndrome and is absent from large population databases (Choi 2004, Tester 2005, Kapplinger 2009). This variant is predicted to cause a frames hift, which alters the protein's amino acid sequence beginning at codon 163 and leads to a premature stop codon 74 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Loss of function variants in KCNQ1 lead to Jervell and Lange-Nielsen syndrome (JLNS) in compound heterozy gous and homozygous individuals, while dominant-negative and loss-of-function va riants in KCNQ1 have been shown to cause dominantly inherited long QT syndrome 1 (also known as Romano-Ward syndrome)in heterozygous individuals. In summary, al though additional studies are required to fully establish its clinical significa nce, this variant meets our criteria to be classified as likely pathogenic (http ://www.partners.org/personalizedmedicine/LMM) based upon its impact to the prote in. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 2021)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501567.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Jun 17, 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: SCV001387688.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 53050). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 53050). This variant is also known as L163FS/X236. This premature translational stop signal has been observed in individuals with sudden unexplained death (PMID: 22677073). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu163Argfs*74) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). (less)
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Pathogenic
(May 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839969.1
First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018 |
Comment:
The c.488del (p.Leu163Argfs*74) variant in the KCNE1 gene has been reported in a patient from a cohort of 388 patients referred for LQTS genetic testing … (more)
The c.488del (p.Leu163Argfs*74) variant in the KCNE1 gene has been reported in a patient from a cohort of 388 patients referred for LQTS genetic testing with a family history of a first degree relative with a cardiac event during swimming [reported as V162fs in PMID 15840476, 15840476]. This variant has not been observed in the ExAC database but has been assessed in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/53050). This one bp deletion in exon 3 results in a frameshift and the creation of a premature stop codon, and is predicted to result in a loss of function of KCNQ1. This variant is thus classified as pathogenic (less)
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Pathogenic
(Feb 08, 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: SCV000234567.10
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function … (more)
Not observed in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15466642, 15840476, 19716085, 19841300, 22677073, 31447099, 30122538, 33087929, 34319147) (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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Exome sequencing and characterization of 49,960 individuals in the UK Biobank. | Van Hout CV | Nature | 2020 | PMID: 33087929 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot. | Sapp JC | American journal of human genetics | 2018 | PMID: 30122538 |
Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. | Tester DJ | Mayo Clinic proceedings | 2012 | PMID: 22677073 |
The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
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 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. | Choi G | Circulation | 2004 | PMID: 15466642 |
Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. | Shalaby FY | Circulation | 1997 | PMID: 9323054 |
Text-mined citations for rs397508112 ...
HelpRecord last updated Feb 28, 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.