ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046003 SCV000074016 pathogenic Long QT syndrome 2020-10-12 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 2020-07-21 criteria provided, single submitter clinical testing 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; Functional studies demonstrate a loss of function of the potassium channel (Huang et al., 2001; Westenskow et al., 2004; Mousavi et al., 2015); This variant is associated with the following publications: (PMID: 24912595, 15051636, 26675252, 23098067, 24606995, 30406014, 26669661, 30609406, 23392653, 11530100, 15935335, 24357532, 19716085, 10704188, 22539601, 14510661, 17470695, 22629021, 21185501, 15840476, 18752142, 11140949, 25705178, 10973849, 26318259, 27451284, 27041150, 27761162, 29033053, 14678125, 30369311, 32383558, 31589614)
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 The p.Q530* pathogenic mutation (also known as c.1588C>T), located in coding exon 12 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1588. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been reported in a number of patients with long QT syndrome, as well as in either the homozygous state or in trans with another pathogenic mutation in patients with Jervell and Lange-Nielsen syndrome (Tranebjaerg L et al. Am J Med Genet. 1999;89:137-46; Huang L et al. Cardiovasc Res. 2001;51:670-80; Ning L et al. Ann Noninvasive Electrocardiol. 2003;8:246-50; Zareba W et al. J Cardiovasc Electrophysiol. 2003;14:1149-53; Westenskow P et al. Circulation. 2004;109:1834-41; Giudicessi JR et al. Circ Cardiovasc Genet. 2013;6:193-200; Torekov SS et al. Diabetes. 2014;63:1315-25). In addition, in vitro assays confirmed the alteration to be non-functional (Huang L et al. Cardiovasc Res. 2001;51:670-80; Wilson AJ et al. Cardiovasc Res. 2005;67:476-86; Harmer SC et al. Biochem J. 2014;462:133-42). In addition to the 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.
Color Health, Inc RCV001188649 SCV001355739 pathogenic Arrhythmia 2021-01-19 criteria provided, single submitter clinical testing This variant creates a premature translation stop signal in exon 12 of the KCNQ1 protein. This variant is expected to result in an absent or non-functional protein product. Experimental functional studies have shown that the variant causes defective trafficking to the cell membrane and non-functional potassium channel (PMID: 15051636, 24912595, 25705178). This variant has been reported in the heterozygous state in more than 50 individuals affected with long QT syndrome (PMID: 10973849, 14678125, 18752142, 19716085, 22629021, 23392653, 24552659, 24606995, 27451284) and in the homozygous or compound heterozygous state in more than 20 individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 10704188, 10973849, 11530100, 14510661, 18752142, 23392653, 22629021). This variant has been identified in 7/251292 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV001029805 SCV001440832 pathogenic Long QT syndrome 1 2019-01-01 criteria provided, single submitter clinical testing
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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