ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.914G>A (p.Trp305Ter)

gnomAD frequency: 0.00001  dbSNP: rs120074186
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000046150 SCV000074163 pathogenic Long QT syndrome 2022-10-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 53124). This premature translational stop signal has been observed in individuals with LQTS (PMID: 12702160; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs120074186, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Trp305*) 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).
GeneDx RCV000254708 SCV000321802 pathogenic not provided 2024-07-18 criteria provided, single submitter clinical testing Reported in one individual with drug induced Torsades de Pointes (PMID: 24223155); Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19862833, 25525159, 19716085, 12702160, 19841298, 29876285, 31447099, 23631430, 23995044, 30930557, 24692356, 23124029, 24223155)
Ambry Genetics RCV000619717 SCV000737508 pathogenic Cardiovascular phenotype 2021-12-03 criteria provided, single submitter clinical testing The p.W305* pathogenic mutation (also known as c.914G>A), located in coding exon 6 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 914. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This alteration has been reported in multiple individuals with long QT syndrome (Chen S. et al. Clin. Genet. 2003;63(4):273-82; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Schwartz PJ et al. Circulation 2009;120(18):1761-7; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000826193 SCV000967743 pathogenic Congenital long QT syndrome 2021-01-06 criteria provided, single submitter clinical testing The p.Trp305X variant in KCNQ1 has been reported in at least 1 individual with long QT syndrome (LQTS) and segregated with disease in at least 3 affected relatives (Chen et al. 2003). It has also been reported by other clinical laboratories in ClinVar (Variation ID 53124) and has been identified in 0.008% (2/24762) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 305, which is predicted to lead to a truncated or absent protein. Loss-of-function variants in KCNQ1 are associated with LQTS (also known as Romano-Ward syndrome) in the heterozygous state and with Jervell and Lange-Nielsen syndrome (JLNS) in the compound heterozygous or homozygous state. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon segregation studies, very low frequency in the general population, and predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PM2_Supporting, PP1_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001841658 SCV001361861 pathogenic Cardiac arrhythmia 2019-07-08 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.914G>A (p.Trp305X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 249180 control chromosomes (gnomAD). c.914G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (Chen_2003, Schwartz_2009, Cuneo_2013, Lieve_2013) and drug-induced Torsades de Pointes (diTdP) (Behr_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health RCV001841658 SCV001734782 pathogenic Cardiac arrhythmia 2023-12-19 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 6 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been shown to segregate with long QT syndrome in three related individuals in a family (PMID: 12702160). This variant has been identified in 5/280572 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.
AiLife Diagnostics, AiLife Diagnostics RCV000254708 SCV002501768 pathogenic not provided 2022-01-12 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496704 SCV002796321 pathogenic Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2 2022-04-29 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000046150 SCV004838808 pathogenic Long QT syndrome 2024-01-08 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 6 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual with sudden death and three individuals with long QT syndrome in one family (PMID: 12702160). This variant has been identified in 5/280572 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.

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