ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.416T>C (p.Leu139Pro) (rs199473460)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046131 SCV000074144 pathogenic Long QT syndrome 2020-06-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 266 of the KCNQ1 protein (p.Leu266Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in numerous individuals and families affected with long QT syndrome and Jervell and Lange-Nielsen syndrome (PMID: 22949429, 17470695, 17905336, 21451124, 1467812, 21118729). ClinVar contains an entry for this variant (Variation ID: 53108). An experimental study, which evaluated the role of this mutation on the function of KCNQ1 channel protein, reported significant effects on several aspects of protein function including a decreased rate of channel activation and deactivation (PMID: 21451124). In summary, this variant is a rare missense change that has been reported in multiple individuals and families affected with a KCNQ1-related disease and has been shown to affect protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182116 SCV000234419 pathogenic not provided 2018-10-23 criteria provided, single submitter clinical testing The pathogenic L266P variant in the KCNQ1 gene has been published in multiple unrelated individuals with LQTS and also has been reported as a founder mutation in families of Northern Irish or Scottish descent (Splawski et al., 2000; Zareba et al., 2003; Tester et al., 2005; Chung et al., 2007; Moss et al., 2007; Kapa et al., 2009; Kapplinger et al., 2009; Gray et al., 2010; Albertella et al., 2011; Giudicessi et al., 2012). L266P has been identified in several unrelated patients referred for LQTS genetic testing at GeneDx and has been classified in ClinVar as a pathogenic or likely pathogenic variant by other clinical laboratories (ClinVar SCV000074144.5; SCV000280164.1; Landrum et al., 2016). Furthermore, L266P was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L266P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this pathogenic variant is located in the S-5 transmembrane domain of the protein, a region in the outer helix of the selectivity filter that is conserved across species (Splawski et al., 2000). It has been reported that variants in this region will most likely disrupt potassium ion transport, further supporting the functional importance of this region of the protein (Splawski et al., 2000; Jons et al., 2011).
Ambry Genetics RCV000250332 SCV000320565 pathogenic Cardiovascular phenotype 2018-07-25 criteria provided, single submitter clinical testing The p.L266P pathogenic mutation (also known as c.797T>C), located in coding exon 6 of the KCNQ1 gene, results from a T to C substitution at nucleotide position 797. The leucine at codon 266 is replaced by proline, an amino acid with similar properties, and is located in the S5 transmembrane spanning region. This mutation has been described as one of the most common causative variants for long QT syndrome (LQTS), having been reported in multiple patients with long QT syndrome (LQTS), numerous patients from LQTS genetic testing cohorts, and patients with Jervell and Lange-Nielsen syndrome who carried a second mutation in KCNQ1 (Splawski I et al. Circulation. 2000;102(10):1178-85; Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Moss A et al. Circulation. 2007;115(19):2481-9; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Rice KS et al. Heart Rhythm. 2011;8(4):551-4; Whiffin N et al. Genet. Med., 2017 Oct;19:1151-1158). In an in vitro study, this variant disrupted channel function, suggesting an association with increased risk for cardiac events (Jons C et al. Sci Transl Med. 2011;3(76):26ra28). Based on internal structural analysis, this variant is predicted to destabilize the transmembrane S5 helix (Long et al. Nature. 2007;450(7168):376-82). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Gharavi Laboratory,Columbia University RCV000182116 SCV000809443 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057763 SCV000089282 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:11668638;PMID:14678125;PMID:15840476;PMID:17905336;PMID:19716085;PMID:19841300;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000182116 SCV000280164 likely pathogenic not provided 2015-04-08 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Leu266Pro Given the strong case data and absence in controls and individuals who are presumed to not have long QT we consider this variant likely disease causing. The variant has been seen in at least 38 unrelated cases of long QT or likely long QT. There is no segregation data available. The variant was first reported by Splawski et al (2000) in one family with long QT syndrome. No specifics of phenotype or segregation were provided, whoever all subjects had a diagnosis of long QT. Subjects were recruited from North America and Europe. Larsen et al (2001) report this variant in a methods paper, noting samples came from Danish LQTS patients and their family members. There is no overlap in authors between Splawski et al and Larsen et al, however given the vagueness of "European recruitment in Splawski et al it is possible they overlap. The same group as Splawski et al later reported on genotype-phenotype correlations, including subjects with this variant, however it is unclear whether they are all from the same family or multiple families or whether they observed segregation with long QT phenotype (Zareba et al 2003, Moss et al 2007). Ackerman's group observed the variant in four unrelated individuals with long QT or suspected long QT referred to their lab for research-based genetic testing (Tester et al 2005). Skinner's group reported the variant in three unrelated patients with long QT syndrome in New Zealand, all of European descent (Chung et al 2007). The variant was reported in 30 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). We did not do an exhaustive literature search. Zareba et al (2003) note this variant as "pre-pore"/N-terminal region. Chung et al (2007) note it is in the S5 domain. In total the variant has not been seen in 60,794 published controls and individuals from publicly available population datasets. The variant was not observed in the following published control samples: 744 (Tester et al 2005), 50 (Chung et al 2007). There is no variation at codon 266 listed in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~60,000 individuals of European, African, Latino and Asian descent (as of April 8th, 2015).

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