ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.573_577del (p.Arg192fs)
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
-
NM_000218.3(KCNQ1):c.573_577del (p.Arg192fs)
Variation ID: 53072 Accession: VCV000053072.55
- Type and length
-
Deletion, 5 bp
- Location
-
Cytogenetic: 11p15.5 11: 2570720-2570724 (GRCh38) [ NCBI UCSC ] 11: 2591950-2591954 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Nov 22, 2014 May 1, 2024 Dec 7, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000218.3:c.573_577del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg192fs frameshift NM_000218.2:c.573_577delGCGCT NP_000209.2:p.Arg192Cysfs frameshift NM_001406836.1:c.573_577delGCGCT NP_001393765.1:p.Arg192Cysfs frameshift NM_001406837.1:c.303_307delGCGCT NP_001393766.1:p.Arg102Cysfs frameshift NM_181798.1:c.192_196delGCGCT frameshift NM_181798.2:c.192_196delGCGCT NP_861463.1:p.Arg65Cysfs frameshift NR_040711.2:n.466_470delGCGCT NC_000011.10:g.2570723_2570727del NC_000011.9:g.2591953_2591957del NG_008935.1:g.130733_130737del LRG_287:g.130733_130737del LRG_287t1:c.573_577del LRG_287p1:p.Arg192fs LRG_287t2:c.192_196del LRG_287p2:p.Arg65fs - Protein change
- R192fs, R65fs
- Other names
- NP_000209.2:p.Arg518Ter
- Canonical SPDI
- NC_000011.10:2570719:GCTGCGCT:GCT
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
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. |
|||
KCNQ1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1702 | 2589 |
Conditions - Germline
Condition
Help
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
Help
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. |
---|---|---|---|---|
not provided (1) |
no classification provided
|
- | RCV000144973.7 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 17, 2023 | RCV000182268.16 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 7, 2023 | RCV000233139.17 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 17, 2023 | RCV000590377.8 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 23, 2023 | RCV000853261.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 8, 2018 | RCV001258104.5 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 28, 2017 | RCV000602841.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV003335078.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 1, 2023 | RCV003591643.1 |
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
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. |
|
---|---|---|---|---|---|
Pathogenic
(Jan 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234571.13
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Observed in the heterozygous state in multiple individuals from different ethnic backgrounds with long QT syndrome (Stattin et al., 2012; Anderson et al., 2014; Seethala … (more)
Observed in the heterozygous state in multiple individuals from different ethnic backgrounds with long QT syndrome (Stattin et al., 2012; Anderson et al., 2014; Seethala et al., 2015; Gaba et al., 2016); Prevalence and haplotype studies suggest it is a founder mutation in the Scandanavian population (Tyson et al., 1997; Winbo et al., 2012); Denoted in published literature as c.735_739delGCGCT, 5 bp deletion of nt 187-191, 572del5, c.572_576del, L191fs/90 and L191fs +90X, due to the use of alternate nomenclature; Not observed at significant frequency 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; Published functional studies demonstrate this variant alone did not produce any significant potassium current and had a mild dominant negative when co-expressed with wild-type KCNQ1 channels (Huang et al., 2001); Reported in ClinVar as pathogenic (ClinVar Variant ID# 53072; ClinVar); This variant is associated with the following publications: (PMID: 15466642, 8528244, 31019026, 11530100, 5923041, 26681611, 9328483, 10704188, 11140949, 23098067, 22539601, 24666684, 26675252, 27451284, 23392653, 22677073, 23631430, 19716085, 10973849, 15840476, 30406014, 30369311, 17470695, 10560595, 25471708, 25991456, 18452873, 19841300, 26318259, 31447099, 33087929, 34319147, 34411974) (less)
|
|
Pathogenic
(Jan 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564240.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The KCNQ1 c.573_577delGCGCT; p.Arg192CysfsTer91 variant (rs397508118), also known as 572del5, 735-739delGCGCT, L191fs/90, or L191fs +90X, is reported in the literature in the homozygous or compound … (more)
The KCNQ1 c.573_577delGCGCT; p.Arg192CysfsTer91 variant (rs397508118), also known as 572del5, 735-739delGCGCT, L191fs/90, or L191fs +90X, is reported in the literature in the homozygous or compound heterozygous state in several individuals and families affected with Jervell and Lange-Nielsen syndrome or in the heterozygous state in individuals with long QT syndrome (Ackerman 1999, Anderson 2015, Giudicessi 2013, Huang 2001), and is a founder variant in the Norwegian population (Tranebjaerg 1999). This variant is also reported in ClinVar (Variation ID: 53072), but is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In vitro functional analyses demonstrate reduced current and a mild dominant negative effect (Huang 2001). Based on available information, this variant is considered to be pathogenic. References: Ackerman MJ et al. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc. 1999 Nov;74(11):1088-94. PMID: 10560595. Anderson HN et al. Marked, transient, emotion-triggered QT accentuation in an adolescent female with type 1 long QT syndrome. Cardiol Young. 2015 Feb;25(2):376-9. PMID: 24666684. Giudicessi JR and Ackerman MJ. Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity. Circ Cardiovasc Genet. 2013 Apr;6(2):193-200. PMID: 23392653. Huang L et al. A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome. Cardiovasc Res. 2001 Sep;51(4):670-80. PMID: 11530100. Tranebjaerg L et al. Jervell and Lange-Nielsen syndrome: a Norwegian perspective. Am J Med Genet. 1999 Sep 24;89(3):137-46. PMID: 10704188. (less)
|
|
Pathogenic
(Dec 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004838759.1
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)
|
Comment:
This variant (also known as 572del5 and c.572_576del in published literature due to the use of alternate nomenclature) deletes 5 nucleotides in exon 3 of … (more)
This variant (also known as 572del5 and c.572_576del in published literature due to the use of alternate nomenclature) deletes 5 nucleotides in exon 3 of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that this variant does not produce any significant potassium current and has a mild dominant negative effect when co-expressed with wild-type KCNQ1 channels in Xenopus laevis oocytes (PMID: 11530100). This variant has been reported in homozygous or compound heterozygous states in many individuals affected with Jervell and Lange-Nielsen syndrome from 15 different families of Norwegian or Swedish ancestry, and in heterozygous state in 3 relatives affected with long QT syndrome and in 29 asymptomatic relatives from these families (PMID: 10704188, 22539601, 25471708, 27451284, 30406014). This variant has also been reported in another 8 unrelated individuals affected with long QT syndrome (PMID: 24666684, 30369311, 31246743, 31520628, 32893267). This variant has been identified in 4/249462 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)
Number of individuals with the variant: 5
|
|
Pathogenic
(May 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695992.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The KCNQ1 c.573_577delGCGCT (p.Arg192Cysfs) variant results in a premature termination codon, predicted to cause a truncated or absent KCNQ1 protein due to nonsense … (more)
Variant summary: The KCNQ1 c.573_577delGCGCT (p.Arg192Cysfs) variant results in a premature termination codon, predicted to cause a truncated or absent KCNQ1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 4/120312 control chromosomes at a frequency of 0.0000332, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0000833). The variant is recurrently reported in patients with JLNS in homozygous as well as heterozygous state. The variant is also reported in heterozygous state in LQTS patients or in individuals suspected of LQTS diagnosis, in individuals with normal or borderline QTS prolongation, atrial fibrillation and sudden unexplained death, suggesting that clinical features associated with a heterozygous c.573_577delGCGCT variant are variable. Functional data are consistent with disease-causing role of this variant. It has also been reported as a probable founder/common mutation in Norway and Sweden causing JLNS. One clinical labs in ClinVar as well as reputable databases have classified it as pathogenic. Taken together, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jun 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital long QT syndrome
Jervell and Lange-Nielsen syndrome
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731601.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Arg192CysfsX91 variant is reported to be a Scandinavian founder variant in KCNQ1 and has been identified in the homozygous or compound heterozygous state in … (more)
The p.Arg192CysfsX91 variant is reported to be a Scandinavian founder variant in KCNQ1 and has been identified in the homozygous or compound heterozygous state in at least 10 individuals from 9 families with Jervell and Lange-Nielsen syndro me (JLNS). Most of the older relatives who were heterozygous carriers of this va riant were asymptomatic with normal QT intervals, while at least 3 had clinical features of long QT syndrome (LQTS; Tranebjareg 1999, Winbo 2012), indicating re duced penetrance. This variant has also been identified in at least 4 unrelated individuals with LQTS (Ackerman 1999, Lieve 2013, Anderson 2015) and has been re ported in ClinVar (Variation ID: 53072). In vitro functional studies provide som e evidence that the p.Arg192CysfsX91 variant may slightly impact protein functio n (Huang 2001). Additionally, this variant has been identified in 4/113014 of Eu ropean chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 192 and leads to a premature termination codon 91 amino a cids downstream. This alteration is then predicted to lead to a truncated or abs ent protein. Loss-of-function variants in KCNQ1 are associated with LQTS (also k nown as Romano-Ward syndrome) in the heterozygous state and with JLNS in the com pound heterozygous or homozygous state. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner with red uced penetrance and JLNS in an autosomal recessive manner. ACMG/AMP criteria: PV S1, PS4, PM2. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Jan 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT Syndrome
Affected status: yes
Allele origin:
germline
|
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995118.1
First in ClinVar: Oct 11, 2019 Last updated: Oct 11, 2019 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Oct 08, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 1
Jervell and Lange-Nielsen syndrome 1
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434950.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.573_577delGCGCT (p. Arg192Cysfs*91) variant in the KCNQ1 gene was predicted to produce a truncated protein. It has been observed in multiple individuals with long … (more)
The c.573_577delGCGCT (p. Arg192Cysfs*91) variant in the KCNQ1 gene was predicted to produce a truncated protein. It has been observed in multiple individuals with long QT syndrome and was segregated in a Norwegian family with Long QT syndrome (PMID: 10704188, 11530100, 23392653). This variant is extremely rare in the general population according to gnomAD database. Therefore, this c.573_577delGCGCT (p. Arg192Cysfs*91) variant in the KCNQ1 gene is classified as pathogenic. (less)
|
|
Pathogenic
(Oct 12, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 1
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Region Ostergotland
Accession: SCV001984981.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
PVS1, PM2, PP5
|
|
Pathogenic
(Oct 25, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023217.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Dec 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000283884.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg192Cysfs*91) 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.Arg192Cysfs*91) 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 (rs764567762, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 10560595, 11530100, 22539601, 23392653, 24666684). ClinVar contains an entry for this variant (Variation ID: 53072). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Nov 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
LONG QT SYNDROME 1
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996087.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This frameshifting variant is predicted to lead to early termination of the KCNQ1 protein. There are multiple reports of the variant by clinical laboratories as … (more)
This frameshifting variant is predicted to lead to early termination of the KCNQ1 protein. There are multiple reports of the variant by clinical laboratories as pathogenic in ClinVar (Variation ID 53072) and in the literature (PMID: 24666684, 11530100, 10560595). Truncating variants in KCNQ1 are established as disease causing, and the variant is predicted by in silico methods to be damaging. Functional characterization of the variant indicated electrophysiological consequences on channel functioning (PMID: 11530100). It is seen in 2 heterozygotes in gnomAD, thus the variant is rare. Based on the combined evidence, the variant is classified as pathogenic. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Mar 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 1
Affected status: yes
Allele origin:
germline
|
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust
Accession: SCV003853457.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
KCNQ1-related disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046104.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This frameshifting variant in exon 3 of 16 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function … (more)
This frameshifting variant in exon 3 of 16 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple individuals with long QT syndrome (PMID: 10560595, 22539601, 24666684, 11530100, 23392653). Functional studies showed the c.573_577del (p.Arg192CysfsTer91) variant causes a dominant-negative effect on KCNQ1 function (PMID: 11530100). The c.573_577del (p.Arg192CysfsTer91) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (4/249462) and thus is presumed to be rare. Based on the available evidence, the c.573_577del (p.Arg192CysfsTer91) variant is classified as Pathogenic. (less)
|
|
Pathogenic
(May 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004358376.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant (also known as 572del5 and c.572_576del in published literature due to the use of alternate nomenclature) deletes 5 nucleotides in exon 3 of … (more)
This variant (also known as 572del5 and c.572_576del in published literature due to the use of alternate nomenclature) deletes 5 nucleotides in exon 3 of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in homozygous or compound heterozygous states in many individuals affected with Jervell and Lange-Nielsen syndrome from 15 different families of Norwegian or Swedish ancestry, and in heterozygous state in 3 relatives affected with long QT syndrome and in 29 asymptomatic relatives from these families (PMID: 10704188, 22539601, 25471708, 27451284, 30406014). This variant has also been reported in another 8 unrelated individuals affected with long QT syndrome (PMID: 24666684, 30369311, 31246743, 31520628, 32893267). This variant has been identified in 4/249462 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)
|
|
Pathogenic
(Jan 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000737838.6
First in ClinVar: Mar 17, 2018 Last updated: May 01, 2024 |
Comment:
The c.573_577delGCGCT pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of 5 nucleotides at positions 573 to 577, … (more)
The c.573_577delGCGCT pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of 5 nucleotides at positions 573 to 577, causing a translational frameshift with a predicted alternate stop codon (p.R192Cfs*91). This alteration has been described in several homozygous and compound heterozygous families with autosomal recessive Jervell and Lange-Nielsen syndrome, and haplotype analysis has suggested a founder mutation effect in Norway (Tranebjaerg L et al. Am J Med Genet. 1999;89:137-46). Among these families, this alteration also was detected in the heterozygous state in multiple unaffected relatives; however, in other studies, this alteration was reported in heterozygous individuals with autosomal dominant long QT syndrome (LQTS) (Ackerman MJ et al. Mayo Clin Proc.1999;74:1088-94; Anderson HN et al. Cardiol Young. 2015;25:376-9), suggesting co-segregation with incomplete penetrance. 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)
|
|
Likely pathogenic
(Sep 22, 2016)
|
no assertion criteria provided
Method: provider interpretation
|
not provided
Affected status: unknown
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924822.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
Testing was performed by GeneDx. We’ve seen this variant in adult in our center with likely long QT syndrome Given the type of variation, the … (more)
Testing was performed by GeneDx. We’ve seen this variant in adult in our center with likely long QT syndrome Given the type of variation, the rarity, and the case data we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There are multiple nonsense and frameshift mutations resulting in premature stop codons listed as pathogenic in HGMD and in the NYU/IRCCS Fondazione Salvatore Maugeri Inherited Arrhythmias Database. Of note, ExAC data suggests KCNQ1 is not tolerant to loss of function variation. Fewer variants of that type are observed in the ExAC data than expected. In Familion's case series, 15% of 199 KCNQ1 variants identified on long QT testing were loss of function (Kapplinger et al 2009). Priori's original series had similar rates (Napolitano et al 2005). We have seen multiple loss of function variants in KCNQ1 that we feel are pathogenic. The variant was reported online in 4 of 59916 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of Sep 22nd, 2016). Specifically, the variant was observed in 4 of 32851 Europeans. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Of note, given the observed Norwegian founder effect the allele frequency in a European sample is not necessarily concerning, since Norwegians may well be included in that sample. (less)
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Jervell and Lange-Nielsen syndrome 1
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000192000.3
First in ClinVar: Nov 22, 2014 Last updated: Oct 01, 2022 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32893267 |
Mothers with long QT syndrome are at increased risk for fetal death: findings from a multicenter international study. | Cuneo BF | American journal of obstetrics and gynecology | 2020 | PMID: 31520628 |
Rapid Whole Genome Sequencing Has Clinical Utility in Children in the PICU. | Sanford EF | Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies | 2019 | PMID: 31246743 |
Epilepsy in patients with long QT syndrome type 1: A Norwegian family. | González A | Epilepsy & behavior case reports | 2018 | PMID: 30406014 |
Genetic and Phenotypic Characterization of Community Hospital Patients With QT Prolongation. | Gibbs C | Journal of the American Heart Association | 2018 | PMID: 30369311 |
Jervell and Lange-Nielsen Syndrome. | Adam MP | - | 2017 | PMID: 20301579 |
The Jervell and Lange-Nielsen syndrome; atrial pacing combined with ß-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome? | Früh A | Heart rhythm | 2016 | PMID: 27451284 |
DNA sequence analysis and genotype-phenotype assessment in 71 patients with syndromic hearing loss or auditory neuropathy. | Tang HY | BMJ open | 2015 | PMID: 25991456 |
Vestibular dysfunction is a clinical feature of the Jervell and Lange-Nielsen Syndrome. | Winbo A | Scandinavian cardiovascular journal : SCJ | 2015 | PMID: 25471708 |
Marked, transient, emotion-triggered QT accentuation in an adolescent female with type 1 long QT syndrome. | Anderson HN | Cardiology in the young | 2015 | PMID: 24666684 |
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 |
Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity. | Giudicessi JR | Circulation. Cardiovascular genetics | 2013 | PMID: 23392653 |
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 |
Prevalence, mutation spectrum, and cardiac phenotype of the Jervell and Lange-Nielsen syndrome in Sweden. | Winbo A | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2012 | PMID: 22539601 |
The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
Prevalence of early-onset atrial fibrillation in congenital long QT syndrome. | Johnson JN | Heart rhythm | 2008 | PMID: 18452873 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome. | Huang L | Cardiovascular research | 2001 | PMID: 11530100 |
Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen. | Tyson J | Human genetics | 2000 | PMID: 11140949 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
Jervell and Lange-Nielsen syndrome: a Norwegian perspective. | Tranebjaerg L | American journal of medical genetics | 1999 | PMID: 10704188 |
Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. | Ackerman MJ | Mayo Clinic proceedings | 1999 | PMID: 10560595 |
IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. | Tyson J | Human molecular genetics | 1997 | PMID: 9328483 |
Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. | Shalaby FY | Circulation | 1997 | PMID: 9323054 |
click to load more click to collapse |
Text-mined citations for rs397508118 ...
HelpRecord last updated May 12, 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.