ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1171C>T (p.Arg391Ter) (rs17215500)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000148548 SCV000074010 pathogenic Long QT syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 518 (p.Arg518*) 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 (PMID: 19862833). This variant is clearly defined as a Jervell and Lange-Nielsen syndrome causative allele (PMID: 10704188, 22539601). It is a founder mutation in the Swedish population, and while this variant has been shown to cause long QT syndrome in addition to Jervell and Lange-Nielsen syndrome (PMID: 23098067), the clinical manifestations of long QT syndrome for heterozygous carriers are typically mild (PMID: 24552659). ClinVar contains an entry for this variant (Variation ID: 3131). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182196 SCV000234499 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing The R518X pathogenic variant in the KCNQ1 gene is well-described in association with autosomal recessive JLNS and has also been reported in cases of autosomal recessive and autosomal dominant LQTS (Larsen et al., 1999; Tranebjaerg et al., 1999; Wei et al., 2000; Splawski et al., 2000; Ning et al., 2000; Berge et al., 2008; Winbo et al., 2012; Früh et al., 2016; Bersell et al., 2016). In addition, R518X has been observed in multiple unrelated individuals referred for LQTS genetic testing at GeneDx. Reduced penetrance and variable expressivity have been reported in individuals heterozygous for this variant and it has been observed that R518X may give rise to a less severe phenotype compared to other molecular causes of autosomal dominant LQTS (Larsen et al., 1999; Huang et al., 2001; Tranebjaerg et al., 1999; Winbo et al., 2014). It has also been suggested that expression of deafness in R518X compound heterozygotes may depend on the nature of the second allele (Larsen et al., 1999; Wei et al., 2000; Giudicessi et al., 2013; Tan et al., 2014). Functional studies propose that R518X may result in nonfunctional channels that lack the trafficking domain and key elements for assembly (Ghosh et al., 2006) and that the behavior of the channels may depend on the relative quantities of variant and wild-type proteins (Huang et al., 2001), though it is not clear how well these studies reproduce in vivo conditions.
Ambry Genetics RCV000251958 SCV000318307 pathogenic Cardiovascular phenotype 2017-06-12 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),Other strong data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000182196 SCV000609857 pathogenic not provided 2017-08-15 criteria provided, single submitter clinical testing
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000515748 SCV000611761 pathogenic Long QT syndrome 1 2017-07-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000614524 SCV000711081 pathogenic Romano-Ward syndrome; Jervell and Lange-Nielsen syndrome 2017-10-17 criteria provided, single submitter clinical testing The p.Arg518X variant in KCNQ1 was reported in the heterozygous state in 6 indiv iduals with autosomal dominant long QT syndrome (LQTS), and in the compound hete rozygous state in 2 siblings with severe autosomal recessive LQTS (Larsen 1999, Stattin 2012). It has also been reported in the compound heterozygous and homozy gous state in >13 individuals with Jervell and Lange-Nielsen syndrome (JLNS), se gregating with disease in >6 individuals from 2 families (Tranebjaerg 1999, Ning 2003, Wimbo 2012, Wimbo 2014). Relatives who were heterozygous carriers of this variant were either clinically asymptomatic for LQTS or had a modestly prolonge d QT interval (Larsen 1999, Ning 2003) suggesting reduced penetrance and variabl e expressivity. This variant has also been reported by other clinical labs in Cl inVar (Variation ID 3131) and has been identified in 0.02% (21/111682) of Europe an chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that fo r diseases with late-onset, reduced penetrance, or recessive inheritance, pathog enic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 518, which i s predicted to lead to a truncated or absent protein. In vitro functional studie s provide support for an impact of the p.Arg518X variant to protein function (Ha rmer 2012, Harmer 2014, Slaats 2015). Loss-of-function variants in KCNQ1 are ass ociated with JLNS in the compound heterozygous or homozygous state and with LQTS (also known as Romano-Ward syndrome) in the heterozygous state. In summary, thi s variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner (ACMG/AMP criteria applied: PVS1, PS4_Moderate, PS3_Supporting) and JLNS in an autosomal recessive manner (ACMG/AMP criteria applied: PVS1, PM2 _Supporting, PS3_Supporting, PM3_Strong) based upon presence in multiple affecte d individuals, segregation and functional studies and predicted impact to the pr otein.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000515748 SCV000778609 pathogenic Long QT syndrome 1 2018-05-08 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000515748 SCV000839975 pathogenic Long QT syndrome 1 2018-02-24 criteria provided, single submitter clinical testing This c.1552C>T (p.Arg518*) variant in exon 12 of the KCNQ1 gene creates a premature translation stop codon and is predicted to result in an absent or disrupted protein product. This variant is well-described in association with autosomal recessive Jervell and Lange-Nielsen syndrome and has also been reported in autosomal recessive and autosomal dominant LQTS (PMID 10482963, 10704188, 10737999, 18752142, 22539601, 24552659, 27451284, and 28438721). Reduced penetrance and variable expressivity have been observed in individuals heterozygous for this variant (10482963, 11530100, and 24552659). This variant is a founder allele in Swedish population (PMID 22539601). Based on these data the p.Arg518* variant in the KCNQ1 gene is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000182196 SCV000884053 pathogenic not provided 2018-06-04 criteria provided, single submitter clinical testing The KCNQ1: p.Arg518Ter variant (rs17215500) has been reported in association with Jervell and Lange-Nielsen syndrome, an autosomal recessive disorder that includes long QT intervals and sensorineural hearing loss (Larsen 1999, Giudicessi 2013 and Wei 2000). It is common in the northern Swedish population due to a founder effect (Winbo 2014). Some carriers have been reported to have long QT intervals and related symptoms. Functional analysis, though, suggests that this variant is loss of function and does not act in the dominant negative manner of missense variants typically associated with Romano Ward syndrome (Huang 2001). In addition, this variant may be associated with digenic LQTS; for example, a symptomatic female patient with a resting QTc of 520ms harbored one copy each of this variant and a pathogenic SCN5A variant (Tan 2014). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.02 percent in the European Non-Finnish population (identified on 21 out of 116,682 chromosomes) and has been reported to the ClinVar database as pathogenic by multiple clinical laboratories. This variant induces a termination codon in exon 12 (of 16 exons), and functional studies demonstrate reduced plasma membrane ion channel localization and activity (Harmer 2014). Overall, the p.Arg518Ter variant is considered to be pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000779058 SCV000915523 pathogenic KCNQ1-Related Disorders 2018-10-23 criteria provided, single submitter clinical testing The KCNQ1 c.1552C>T (p.Arg518Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of available literature, the p.Arg518Ter variant has been identified in at least 111 individuals with KCNQ1-related disorders including at least eight in a homozygous state, at least 10 in a compound heterozygous state, and 93 in a heterozygous state (Larsen et al. 1999; Wei et al. 2000; Stattin et al. 2012; Giudicessi et al. 2013; Winbo et al. 2014). The variant was also found in two unaffected individuals in a heterozygous state (Larsen et al. 1999; Wei et al. 2000). The p.Arg518Ter variant was absent from 200 control chromosomes and is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. This variant has been classified as a founder variant from a specific region of Sweden (Winbo et al. 2015) but has also been detected in other populations (Larsen et al. 1999; Wei et al. 2000; Giudicessi et al. 2013). Individuals carrying the variant in a compound heterozygous or homozygous state have a more severe phenotype compared to those with the variant in a heterozygous state (Winbo et al. 2015). To assess the functional effects of the p.Arg518Ter variant, fluorescently labelled KCNQ1 variant constructs were transfected in CHO-K1 cells and confocal microscopy was used to visualize localization of channel complexes. Two studies demonstrated that channel trafficking was disrupted in the presence of the variant whereby a high concentration of the complexes was retained in the endoplasmic reticulum (Wilson et al. 2005; Harmer et al. 2014). In addition, whole-cell patch clamp experiments were used to evaluate current flow and demonstrated that the p.Arg518Ter variant did not produce any current (Ghosh et al. 2006). Based on the collective evidence, the p.Arg518Ter variant is classified as pathogenic for KCNQ1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000148548 SCV000919561 pathogenic Long QT syndrome 2018-10-16 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.1552C>T (p.Arg518X) 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, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00011 in 246226 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in KCNQ1 causing autosomal recessive LQTS (0.00011 vs 0.013), allowing no conclusion about variant significance. The variant, c.1552C>T, has been reported in the literature as a founder mutation in the Swedish population, in several homozygous and compound heterozygous individuals, who were affected with autosomal recessive long QT syndrome (LQTS) with intact auditory phenotype or with deafness (later designated as Jervell and Lange-Nielsen syndrome) (Larsen 1999, Giudicessi 2013, Winbo 2012). In these reports, family members, who were heterozygous carriers of the variant, were typically clinically asymptomatic, with a mildly prolonged QT interval detected by EKG; although rare cases of symptomatic long QT syndrome (LQTS) with intact auditory phenotype (denoted as Romano-Ward syndrome) were also reported (Winbo 2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating non-functional channels when the variant protein was expressed alone; while co-expression of the variant protein with the wild type channel did not indicate dominant negative effect (Mousavi Nik 2015). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for autosomal recessive long QT syndrome.
OMIM RCV000003279 SCV000023437 pathogenic Long QT syndrome 1, recessive 2003-05-08 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148548 SCV000190261 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000182196 SCV000924829 pathogenic not provided 2017-07-11 no assertion criteria provided provider interpretation

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