ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.364dup (p.Cys122fs)
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.364dup (p.Cys122fs)
Variation ID: 200915 Accession: VCV000200915.32
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2445461-2445462 (GRCh38) [ NCBI UCSC ] 11: 2466691-2466692 (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 5, 2015 Feb 14, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.364dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Cys122fs frameshift NM_000218.2:c.364dupT NC_000011.10:g.2445462dup NC_000011.9:g.2466692dup NG_008935.1:g.5472dup LRG_287:g.5472dup - Protein change
- C122fs
- Other names
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- Canonical SPDI
- NC_000011.10:2445461:T:TT
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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) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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
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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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 12, 2019 | RCV000193564.8 | |
Pathogenic (1) |
criteria provided, single submitter
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May 8, 2017 | RCV000182336.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 13, 2024 | RCV001385666.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2023 | RCV003390905.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2019 | RCV002453656.1 |
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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Pathogenic
(Mar 04, 2015)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV000247662.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(May 08, 2017)
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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: SCV000234639.10
First in ClinVar: Jul 05, 2015 Last updated: Jul 24, 2016 |
Comment:
The c.364dupT pathogenic variant in the KCNQ1 gene (also reported as K121fs+162X, 365insT, Ins G 2025-2026, and K121fs/629 due to alternative nomenclature) has previously been … (more)
The c.364dupT pathogenic variant in the KCNQ1 gene (also reported as K121fs+162X, 365insT, Ins G 2025-2026, and K121fs/629 due to alternative nomenclature) has previously been reported in individuals referred for LQTS genetic testing (Tester et al., 2005; Kapplinger et al., 2009). The c.364dupT variant causes a shift in reading frame starting at codon cysteine 122, changing it to a leucine, and creating a premature stop codon at position 163 of the new reading frame, denoted p.Cys122LeufsX163. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other downstream frameshift variants in the KCNQ1 gene have been reported in Human Gene Mutation Database in association with LQTS and JLNS (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.364dupT variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). (less)
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Pathogenic
(Aug 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369497.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP4.
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Pathogenic
(Jun 18, 2019)
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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: SCV002613848.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.364dupT pathogenic mutation, located in coding exon 1 of the KCNQ1 gene, results from a duplication of T at nucleotide position 364, causing a … (more)
The c.364dupT pathogenic mutation, located in coding exon 1 of the KCNQ1 gene, results from a duplication of T at nucleotide position 364, causing a translational frameshift with a predicted alternate stop codon (p.C122Lfs*163). This alteration has been detected in the homozygous state in a child of consanguineous parents who was reported to have Jervell and Lange-Nielsen syndrome. The parents were reported to have normal ECGs (Jacobson D et al. Paediatr Child Health, 2014 Mar;19:123-4). This alteration (also referred to as K121fs/629* and 365insT) has also been detected in long QT syndrome genetic testing cohorts; however, details were limited (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). 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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Pathogenic
(Jul 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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KCNQ1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120824.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The KCNQ1 c.364dupT variant is predicted to result in a frameshift and premature protein termination (p.Cys122Leufs*163). This variant has been reported in multiple individuals with … (more)
The KCNQ1 c.364dupT variant is predicted to result in a frameshift and premature protein termination (p.Cys122Leufs*163). This variant has been reported in multiple individuals with long QT syndrome in both the heterozygous and homozygous state (described as InsG 2025-2026 K121fs/629* in Tester et al. 2005. PubMed ID: 15840476; Schwartz et al. 2021. PubMed ID: 34505893; described as c.365insT in Kapplinger et al. 2009. PubMed ID: 19716085; Whiffin et al. 2019. PubMed ID: 30609406; Jacobson et al. 2014. PubMed ID: 24665220). This variant is reported in 0.017% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2466691-A-AT). Frameshift variants in KCNQ1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jan 13, 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: SCV001585608.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys122Leufs*163) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Cys122Leufs*163) 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). This variant is present in population databases (rs397508109, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of long QT syndrome (PMID: 15840476). This variant is also known as Ins G 2025-2026 (K121fs/629*). ClinVar contains an entry for this variant (Variation ID: 200915). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 01, 2013)
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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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Arcensus
Accession: SCV002564602.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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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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Using High-Resolution Variant Frequencies Empowers Clinical Genome Interpretation and Enables Investigation of Genetic Architecture. | Whiffin N | American journal of human genetics | 2019 | PMID: 30609406 |
Case 1: An infant with a low heart rate. | Jacobson D | Paediatrics & child health | 2014 | PMID: 24665220 |
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 |
Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. | Shalaby FY | Circulation | 1997 | PMID: 9323054 |
Text-mined citations for rs397508109 ...
HelpRecord last updated Mar 11, 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.