ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.192_196del (p.Arg65fs) (rs397508118)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182268 SCV000234571 pathogenic not provided 2016-10-19 criteria provided, single submitter clinical testing The c.573_577delGCGCT mutation in the KCNQ1 gene was initially reported as a homozygous mutation in multiple Norwegian individuals with autosomal recessive Jervell Lange-Nielsen (JLN) syndrome, with haplotype analysis indicating a shared haplotype and founder mutation effect (Tranebjaerg L et al., 1999). In clinical evaluation of the family members of these children with JLN, relatives who were heterozygous carriers of the c.573_577delGCGCT mutation were frequently asymptomatic with normal QT intervals, however at least one heterozygous carrier exhibited a prolonged QT interval on ECG (Tranebjaerg L et al., 1999). Heterozygosity for c.573_577delGCGCT has been subsequently reported in an infant with fetal bradycardia, a prolonged QT interval at age 2 months, and family history of sudden death (Ackerman M et al., 1999). These findings indicates the clinical features associated with a heterozygous c.573_577delGCGCT mutation are variable (Ackerman M et al., 1999). Of note, in these publications the c.573_577delGCGCT mutation is reported as 572_576delGCGCT and 735_739delGCGCT, due to alternative nomenclature (Tranebjaerg L et al., 1999; Ackerman M et al., 1999). The c.573_577delGCGCT mutation causes a shift in the reading frame starting at codon Arginine 192, changing it to a Cysteine and creating a premature stop codon at position 91 of the new reading frame. The c.573_577delGCGCT mutation is located between the S2 and S3 domains, and is expected to result in an abnormal, truncated protein or an absence of protein from this allele due to mRNA decay. The c.573_577delGCGCT mutation has been observed in other individuals tested at GeneDx.
Invitae RCV000233139 SCV000283884 pathogenic Long QT syndrome 2018-11-16 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.
Integrated Genetics/Laboratory Corporation of America 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 (http://gnomad.broadinstitute.org). 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 2016-12-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
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.
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 (http://exac.broadinstitute.org/), 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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