ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.332A>G (p.Tyr111Cys)
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.332A>G (p.Tyr111Cys)
Variation ID: 53035 Accession: VCV000053035.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2445430 (GRCh38) [ NCBI UCSC ] 11: 2466660 (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 Apr 15, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.332A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Tyr111Cys missense NC_000011.10:g.2445430A>G NC_000011.9:g.2466660A>G NG_008935.1:g.5440A>G LRG_287:g.5440A>G LRG_287t1:c.332A>G LRG_287p1:p.Tyr111Cys P51787:p.Tyr111Cys - Protein change
- Y111C
- Other names
- p.Y111C:TAC>TGC
- Canonical SPDI
- NC_000011.10:2445429:A:G
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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 0.00001
Exome Aggregation Consortium (ExAC) 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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not provided (1) |
no classification provided
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- | RCV000057659.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000182260.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 30, 2023 | RCV002513652.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 17, 2018 | RCV002321544.1 |
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
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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
(Aug 17, 2018)
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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: SCV002606259.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.Y111C pathogenic mutation (also known as c.332A>G), located in coding exon 1 of the KCNQ1 gene, results from an A to G substitution at … (more)
The p.Y111C pathogenic mutation (also known as c.332A>G), located in coding exon 1 of the KCNQ1 gene, results from an A to G substitution at nucleotide position 332. The tyrosine at codon 111 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in numerous individuals with long QT syndrome and is a founder mutation in the Swedish population (Splawski I et al. Circulation, 2000 Sep;102:1178-85; Dahimène S et al. Circ. Res., 2006 Nov;99:1076-83; Winbo A et al. Circ Cardiovasc Genet, 2009 Dec;2:558-64; Winbo A et al. Europace, 2012 Dec;14:1799-806; Stattin EL et al. BMC Cardiovasc Disord, 2012 Oct;12:95). In addition, this mutation was identified in the homozygous state in an individual with Jervell and Lange-Nielsen Syndrome (Winbo A et al. Circ Arrhythm Electrophysiol, 2015 Aug;8:806-14). Functional studies have demonstrated that this mutation results in no cell surface expression or potassium current, with the protein retained in the endoplasmic reticulum which is degraded more rapidly compared to wild type (Peroz D et al. J. Biol. Chem., 2009 Feb;284:5250-6; Dahimène S et al. Circ. Res., 2006 Nov;99:1076-83). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 10, 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: SCV000234563.12
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Haplotype analysis was performed using a cohort of 26 Swedish probands, 21 family members, and 84 healthy controls; the authors concluded the Y111C variant originated … (more)
Haplotype analysis was performed using a cohort of 26 Swedish probands, 21 family members, and 84 healthy controls; the authors concluded the Y111C variant originated 600 years ago in the Northern River Valley population (Winbo et al., 2011); Reported to be homozygous in a female with JLNS (Winbo et al., 2012); Identified in numerous patients referred for LQTS genetic testing at GeneDx; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Functional studies have demonstrated that Y111C, which is located in the N-terminal region of the protein, alters a motif that plays a key role in intracellular trafficking of the potassium channel, thus trapping the protein in the endoplasmic reticulum and rendering the channels inactive (Dahimene et al., 2006; Peroz et al., 2009, Winbo et al., 2009; Lee et al., 2020); This variant is associated with the following publications: (PMID: 19008479, 23098067, 27936942, 30847666, 24052033, 19114714, 17053194, 19716085, 20031635, 10973849, 28720088, 30571187, 26019114, 22581653, 22539601, 29532034, 21129503, 29270100, 32383558, 32173736, 33963564, 34761968, 34505893) (less)
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Pathogenic
(Sep 30, 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: SCV003439745.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 111 of the KCNQ1 protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 111 of the KCNQ1 protein (p.Tyr111Cys). This variant is present in population databases (rs199472678, gnomAD 0.002%). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 10973849, 20031635, 21129503, 22539601). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53035). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 17053194, 19114714, 29532034). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004704473.2
First in ClinVar: Mar 10, 2024 Last updated: Apr 15, 2024 |
Comment:
KCNQ1: PP1:Strong, PM1, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting
Number of individuals with the variant: 2
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Pathogenic
(Nov 13, 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: SCV000280152.1
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 p.Tyr111Cys This variant has been reported in at least 46 unrelated cases with Long QT Syndrome, with strong segregation data in a founder population. Splawski et al (2000) first reported p.Tyr111Cys in a 36 yo North American female who presented with a history of over 30 syncopal episodes and a QTC of 520ms. The syncopal episodes were triggered by stress. In 2009 Kapplinger et al reported 5 unrelated case with the variant out or 2500 cases sent to Transgenomic Labs for testing between May 2004 and October 2008. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). That same year Winbo et al (2009) reported of 15 probands with the variant and 80 related carriers (mean QTc 481ms with prolonged QTc in 86% of carriers), all were of Swedish descent. Winbo et al demonstrated that p.Tyr111Cys is a founder mutation in the Swedish population. Two years later Winbo et al (2011) reported 37 unrelated cases with p.Tyr111Cys and a total of 170 carriers (cases presumably overlap with WInbo et al 2009, Diamant et al 2013, by the same group). The same group reported that p.Tyr111Cys was observed in 20 of 200 unrelated long QT cases (presumably overlapping with their other reported cases). Winbo et al (2009) found that the event rate was lower in carriers of p.Tyr111Cys than in other KCNQ1 carriers. The Swedish group also reported a patient with JLNS who was homozygous for this variant (Winbo et al 2012). Ackerman’s group observed the variant in a 3yo that died suddenly in his sleep, with a history of syncope and a negative autopsy. Laksman et al (2014) report a patient with long QT and this variant, however sequencing was done in a clinical genetic testing lab so that may overlap with the Kapplinger et al (2009) cases. Crotti et al (2012) reported two unrelated individuals with this variant recruited in either Italy or South Africa, however it is not clear if they have phenotypic evidence of long QT syndrome. This is a semi conservative amino acid change with a large, polar Tyrosine replaced with a medium sized, polar Cysteine. The amino acid change occurs at the N-terminal of the KCNQ1 protein. In silico (SIFT, PolyPhen 2) analysis predict the amino acid change to be deleterious and probably damaging to the resulting protein. Missense variants in nearby codons (p.His105Leu, p.Leu114Pro, p.Glu115Gly, p.Pro117Leu) have been reported in association with LQTS. This variant is listed in the hearing.harvard database. There are no functional studies involving mouse models. However Dahieme et al (2006) did show that cardiomyocites with the variant have impaired protein trafficking and malfunctioning potassium channel subunits. In total the variant has not been seen in ~8300 individuals from published control samples and publicly available general population datasets. Splawski et al (2000) report that p.Tyr111Cys was absent in 200 presumably healthy controls whose ancestry was not specified. Kapplinger et al (2009) reported that p.Tyr111Cys was not observed in 1300 presumably healthy controls (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). Tester et al (2012) did not observe the variant in and additional 200 controls. The variant was not observed by Stattin et al (2012) in 100 Swedish controls. The variant is listed in dbSNP with the rs199472678 with submission only from a locus-specific database; there is no allele frequency data available. The variant was not observed in the 1000 genomes dataset. In addition there is no variation at codon 111 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of September 23rd 2014). (less)
Number of individuals with the variant: 46
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089178.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:17053194;PMID:19114714;PMID:19716085;PMID:20031635;PMID:21129503;PMID:22539601). This is a literature report, and does not necessarily … (more)
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:17053194;PMID:19114714;PMID:19716085;PMID:20031635;PMID:21129503;PMID:22539601). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (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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Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations. | Huang H | Science advances | 2018 | PMID: 29532034 |
Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene. | Diamant UB | Journal of applied physiology (Bethesda, Md. : 1985) | 2013 | PMID: 24052033 |
Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing. | Stattin EL | BMC cardiovascular disorders | 2012 | PMID: 23098067 |
Paralogous annotation of disease-causing variants in long QT syndrome genes. | Ware JS | Human mutation | 2012 | PMID: 22581653 |
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 |
Origin of the Swedish long QT syndrome Y111C/KCNQ1 founder mutation. | Winbo A | Heart rhythm | 2011 | PMID: 21129503 |
Low incidence of sudden cardiac death in a Swedish Y111C type 1 long-QT syndrome population. | Winbo A | Circulation. Cardiovascular genetics | 2009 | PMID: 20031635 |
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 |
LQT1-associated mutations increase KCNQ1 proteasomal degradation independently of Derlin-1. | Peroz D | The Journal of biological chemistry | 2009 | PMID: 19114714 |
The N-terminal juxtamembranous domain of KCNQ1 is critical for channel surface expression: implications in the Romano-Ward LQT1 syndrome. | Dahimène S | Circulation research | 2006 | PMID: 17053194 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
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Text-mined citations for rs199472678 ...
HelpRecord last updated Apr 15, 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.