ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1207C>T (p.Gln403Ter) (rs397508097)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046003 SCV000074016 pathogenic Long QT syndrome 2019-09-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 530 (p.Gln530*) of 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. This particular variant has been reported in the heterozygous state in multiple individuals with long QT syndrome (PMID: 14678125, 19716085, 24606995) and in the homozygous or compound heterozygous state in several individuals with Jervell and Lange-Nielsen syndrome (PMID: 11530100, 14510661, 23392653, 22629021). This variant has been confirmed in experimental assays to be non-functional (PMID: 15051636, 24912595). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182204 SCV000234507 pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing The Q530X pathogenic variant in the KCNQ1 gene has previously been reported in heterozygous individuals with autosomal dominant LQTS (Splawski et al., 2000; Zareba et al., 2003; Berge et al., 2008; Kapplinger at al., 2009; Christiansen et al., 2014) and in homozygous or compound heterozygous individuals with autosomal recessive JLNS (Tranebjaerg et al., 1999; Huang et al., 2001; Ning et al., 2003; Giudicessi et al., 2013; Früh et al., 2016). This variant has been identified as a founder mutation in the Swedish population (Stattin et al., 2012; Winbo et al., 2012). Q530X has also been identified in multiple unrelated individuals diagnosed with LQTS referred for genetic testing at GeneDx. In addition, the Q530X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Q530X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Functional studies demonstrate that Q530X results in a loss of function of the potassium channel (Huang et al., 2001; Westenskow et al., 2004; Mousavi et al., 2015). Finally, multiple other downstream nonsense variants in the KCNQ1 gene have been reported in Human Gene Mutation Database in association with LQTS (Stenson et al., 2014). In summary, Q530X in theKCNQ1 gene is interpreted as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000515204 SCV000611204 pathogenic Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome 2 2017-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619891 SCV000738152 pathogenic Cardiovascular phenotype 2018-09-18 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV001188649 SCV001355739 pathogenic Arrhythmia 2020-02-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000046003 SCV001360700 pathogenic Long QT syndrome 2019-09-25 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.1588C>T (p.Gln530X) 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. The variant allele was found at a frequency of 2.8e-05 in 251292 control chromosomes (gnomAD). c.1588C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome as well as Lange-Nielsen Syndrome (eg. Itoh_2016, Mullally_2013, Tranebjaerg_1999). These data indicate that the variant is very likely to be associated with disease. Functional studies showed the variant did not yield any detectable potassium channel current (Mousavi Nik_2015). Five ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Gharavi Laboratory,Columbia University RCV000182204 SCV000809458 pathogenic not provided 2018-09-16 no assertion criteria provided research
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV001029805 SCV001192586 pathogenic Long QT syndrome 1 2019-06-25 no assertion criteria provided clinical testing

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