Submissions for variant NM_000218.3(KCNQ1):c.1588C>T (p.Gln530Ter)

gnomAD frequency: 0.00001  dbSNP: rs397508097

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046003	SCV000074016	pathogenic	Long QT syndrome	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln530*) 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 (rs397508097, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 11530100, 14510661, 14678125, 15051636, 19716085, 22629021, 23392653, 24606995, 24912595). ClinVar contains an entry for this variant (Variation ID: 52996). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000182204	SCV000234507	pathogenic	not provided	2022-04-19	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; This variant is associated with the following publications: (PMID: 24912595, 15051636, 26675252, 23098067, 24606995, 30406014, 26669661, 30609406, 32383558, 33087929, 23392653, 15935335, 24357532, 19716085, 10704188, 22539601, 14510661, 17470695, 22629021, 21185501, 15840476, 18752142, 11140949, 25705178, 10973849, 26318259, 27451284, 27041150, 27761162, 29033053, 14678125, 30369311, 31589614, 11530100, 34319147)
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 type 2	2021-11-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619891	SCV000738152	pathogenic	Cardiovascular phenotype	2021-11-24	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 Diagnostics, LLC DBA Color Health	RCV001841634	SCV001355739	pathogenic	Cardiac arrhythmia	2023-04-18	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. 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
AiLife Diagnostics, AiLife Diagnostics	RCV000182204	SCV002501389	pathogenic	not provided	2021-08-25	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Region Ostergotland	RCV001029805	SCV002522541	pathogenic	Long QT syndrome 1	2019-07-03	criteria provided, single submitter	clinical testing	PVS1, PS3, PS4, PP5
PreventionGenetics, part of Exact Sciences	RCV004528255	SCV004103929	pathogenic	KCNQ1-related disorder	2023-10-03	criteria provided, single submitter	clinical testing	The KCNQ1 c.1588C>T variant is predicted to result in premature protein termination (p.Gln530*). This variant has been reported in the homozygous and compound heterozygous state in individuals with Jervell and Lange-Nielsen syndrome (Tranebjaerg et al. 1999. PubMed ID: 10704188; Westenskow et al. 2004. PubMed ID: 15051636) and in the heterozygous state in individuals with long QT syndrome (Wilson et al. 2005. PubMed ID: 15935335; Table S1, Kapplinger et al. 2009. PubMed ID: 19716085). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2790147-C-T) and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52996/). Nonsense variants in KCNQ1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182204	SCV004226842	pathogenic	not provided	2023-05-04	criteria provided, single submitter	clinical testing	PM2_supporting, PS3_moderate, PS4, PVS1
All of Us Research Program, National Institutes of Health	RCV000046003	SCV004836460	pathogenic	Long QT syndrome	2024-09-24	criteria provided, single submitter	clinical testing	The c.1588C>T (p.Gln530*) variant of the KCNQ1 gene creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been identified in heterozygous, compound heterozygous or homozygous status in numerous individuals (>20) with dominant Long QT syndrome as well as recessive Jervell and Lange-Nielsen Syndrome (PMID:10973849, 23174487, 26669661, 11530100, 15051636, 14678125, 18752142, 23392653, 25705178). Loss of function variants are known to be pathogenic for KCNQ1 (PMID: 26669661, 29532034, 23098067). In-vitro assays using Chinese Hamster Ovary cells transfected with mutant plasmid and Xenopus laevis oocyte studies suggest that this variant causes defective trafficking to the cell membrane and non-functional potassium channel (PMID: 15051636, 24912595, 25705178). Truncating variants downstream of this variant are reported in individuals with Long QT syndrome (PMID:19841300, 27871843, 19716085). This variant is found to be rare (7/251292) in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 52996). Therefore, the c.1588C>T (p.Gln530*) variant in the KCNQ1 gene is classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000182204	SCV005198552	pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001029805	SCV005400436	pathogenic	Long QT syndrome 1	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome 2 (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome 1 (LQTS, MIM#192500), familial atrial fibrillation 3 (MIM#607554) as well as Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterised by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (7 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in many individuals with KCNQ1-related features, including in heterozygous individuals with long QT syndrome and individuals with autosomal recessive Jervell and Lange-Nielsen syndrome (ClinVar, VCGS internal database). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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
GeneReviews	RCV001847642	SCV002106355	not provided	Jervell and Lange-Nielsen syndrome 1		no assertion provided	literature only