ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.573_577del (p.Arg192fs) (rs397508118)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182268 SCV000234571 pathogenic not provided 2021-05-21 criteria provided, single submitter clinical testing Observed in the heterozygous state in multiple individuals from different ethnic backgrounds with long QT syndrome (Stattin et al., 2012; Anderson et al., 2014; Seethala et al., 2015; Gaba et al., 2016); Prevalence and haplotype studies suggest it is a founder mutation in the Scandanavian population (Tyson et al., 1997; Winbo et al., 2012); Denoted in published literature as c.735_739delGCGCT, 5 bp deletion of nt 187-191, 572del5, c.572_576del, L191fs/90 and L191fs +90X, due to the use of alternate nomenclature; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift 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; Published functional studies demonstrate this variant alone did not produce any significant potassium current and had a mild dominant negative when co-expressed with wild-type KCNQ1 channels (Huang et al., 2001); Reported in ClinVar as pathogenic (ClinVar Variant ID# 53072; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31447099, 26318259, 19841300, 18452873, 25991456, 25471708, 10560595, 17470695, 30369311, 30406014, 15840476, 10973849, 19716085, 23631430, 22677073, 11530100, 23392653, 27451284, 26681611, 26675252, 24666684, 22539601, 23098067, 11140949, 10704188, 9328483, 5923041, 15466642, 8528244, 31019026)
Invitae RCV000233139 SCV000283884 pathogenic Long QT syndrome 2020-10-15 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 3 of the KCNQ1 mRNA (c.573_577delGCGCT), causing a frameshift at codon 192. This creates a premature translational stop signal (p.Arg192Cysfs*91) and is expected to result in an absent or disrupted protein product. Truncating variants in KCNQ1 are known to be pathogenic. This particular truncation has been reported in the literature (PMID: 10560595, 11530100, 22539601, 23392653, 24666684). ClinVar contains an entry for this variant (Variation ID: 53072). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590377 SCV000695992 pathogenic Cardiovascular phenotype 2016-05-17 criteria provided, single submitter clinical testing Variant summary: The KCNQ1 c.573_577delGCGCT (p.Arg192Cysfs) variant results in a premature termination codon, predicted to cause a truncated or absent KCNQ1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 4/120312 control chromosomes at a frequency of 0.0000332, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0000833). The variant is recurrently reported in patients with JLNS in homozygous as well as heterozygous state. The variant is also reported in heterozygous state in LQTS patients or in individuals suspected of LQTS diagnosis, in individuals with normal or borderline QTS prolongation, atrial fibrillation and sudden unexplained death, suggesting that clinical features associated with a heterozygous c.573_577delGCGCT variant are variable. Functional data are consistent with disease-causing role of this variant. It has also been reported as a probable founder/common mutation in Norway and Sweden causing JLNS. One clinical labs in ClinVar as well as reputable databases have classified it as pathogenic. Taken together, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000602841 SCV000731601 pathogenic Congenital long QT syndrome; Jervell and Lange-Nielsen syndrome 2017-06-28 criteria provided, single submitter clinical testing The p.Arg192CysfsX91 variant is reported to be a Scandinavian founder variant in KCNQ1 and has been identified in the homozygous or compound heterozygous state in at least 10 individuals from 9 families with Jervell and Lange-Nielsen syndro me (JLNS). Most of the older relatives who were heterozygous carriers of this va riant were asymptomatic with normal QT intervals, while at least 3 had clinical features of long QT syndrome (LQTS; Tranebjareg 1999, Winbo 2012), indicating re duced penetrance. This variant has also been identified in at least 4 unrelated individuals with LQTS (Ackerman 1999, Lieve 2013, Anderson 2015) and has been re ported in ClinVar (Variation ID: 53072). In vitro functional studies provide som e evidence that the p.Arg192CysfsX91 variant may slightly impact protein functio n (Huang 2001). Additionally, this variant has been identified in 4/113014 of Eu ropean chromosomes by gnomAD ( This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 192 and leads to a premature termination codon 91 amino a cids downstream. This alteration is then predicted to lead to a truncated or abs ent protein. Loss-of-function variants in KCNQ1 are associated with LQTS (also k nown as Romano-Ward syndrome) in the heterozygous state and with JLNS in the com pound heterozygous or homozygous state. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner with red uced penetrance and JLNS in an autosomal recessive manner. ACMG/AMP criteria: PV S1, PS4, PM2.
Ambry Genetics RCV000590377 SCV000737838 pathogenic Cardiovascular phenotype 2019-01-24 criteria provided, single submitter clinical testing The c.573_577delGCGCT pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of 5 nucleotides at positions 573 to 577, causing a translational frameshift with a predicted alternate stop codon (p.R192Cfs*91). This alteration has been described in several homozygous and compound heterozygous families with autosomal recessive Jervell and Lange-Nielsen syndrome, and haplotype analysis has suggested a founder mutation effect in Norway (Tranebjaerg L et al. Am J Med Genet. 1999;89:137-46). Among these families, this alteration also was detected in the heterozygous state in multiple unaffected relatives; however, in other studies, this alteration was reported in heterozygous individuals with autosomal dominant long QT syndrome (LQTS) (Ackerman MJ et al. Mayo Clin Proc.1999;74:1088-94; Anderson HN et al. Cardiol Young. 2015;25:376-9), suggesting co-segregation with incomplete penetrance. 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.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000233139 SCV000995118 pathogenic Long QT syndrome 2018-01-23 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853261 SCV000996087 pathogenic Long QT syndrome 1 2017-11-30 criteria provided, single submitter clinical testing This frameshifting variant is predicted to lead to early termination of the KCNQ1 protein. There are multiple reports of the variant by clinical laboratories as pathogenic in ClinVar (Variation ID 53072) and in the literature (PMID: 24666684, 11530100, 10560595). Truncating variants in KCNQ1 are established as disease causing, and the variant is predicted by in silico methods to be damaging. Functional characterization of the variant indicated electrophysiological consequences on channel functioning (PMID: 11530100). It is seen in 2 heterozygotes in gnomAD, thus the variant is rare. Based on the combined evidence, the variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258104 SCV001434950 pathogenic Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1 2018-10-08 criteria provided, single submitter clinical testing The c.573_577delGCGCT (p. Arg192Cysfs*91) variant in the KCNQ1 gene was predicted to produce a truncated protein. It has been observed in multiple individuals with long QT syndrome and was segregated in a Norwegian family with Long QT syndrome (PMID: 10704188, 11530100, 23392653). This variant is extremely rare in the general population according to gnomAD database. Therefore, this c.573_577delGCGCT (p. Arg192Cysfs*91) variant in the KCNQ1 gene is classified as pathogenic.
GeneReviews RCV000144973 SCV000192000 pathogenic Jervell and Lange-Nielsen syndrome 1 2014-11-20 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000182268 SCV000924822 likely pathogenic not provided 2016-09-22 no assertion criteria provided provider interpretation Testing was performed by GeneDx. We’ve seen this variant in adult in our center with likely long QT syndrome Given the type of variation, the rarity, and the case data we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There are multiple nonsense and frameshift mutations resulting in premature stop codons listed as pathogenic in HGMD and in the NYU/IRCCS Fondazione Salvatore Maugeri Inherited Arrhythmias Database. Of note, ExAC data suggests KCNQ1 is not tolerant to loss of function variation. Fewer variants of that type are observed in the ExAC data than expected. In Familion's case series, 15% of 199 KCNQ1 variants identified on long QT testing were loss of function (Kapplinger et al 2009). Priori's original series had similar rates (Napolitano et al 2005). We have seen multiple loss of function variants in KCNQ1 that we feel are pathogenic. The variant was reported online in 4 of 59916 individuals in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of Sep 22nd, 2016). Specifically, the variant was observed in 4 of 32851 Europeans. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Of note, given the observed Norwegian founder effect the allele frequency in a European sample is not necessarily concerning, since Norwegians may well be included in that sample.

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