ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1387G>A (p.Ala463Thr) (rs199472813)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182224 SCV000234527 likely pathogenic not provided 2018-04-27 criteria provided, single submitter clinical testing The A590T likely pathogenic variant has been identified in the KCNQ1 gene. This variant has previously been reported in association with sinus bradycardia and LQTS or suspected LQTS (Lupoglazoff et al., 2004; Tester et al., 2005; Kapa et al., 2009). This variant has also been observed in other unrelated individuals referred for LQTS genetic testing at GeneDx, and was found to segregate with disease in at least three affected relatives from one family. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The A590T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although in silico analyses support that this variant does not alter protein structure/function, functional studies by Kinoshita et al. (2014) demonstrated that the A590T variant causes a reduction in potassium ion current density and a shift of the current–voltage relation of channel activation. Also, immunocytochemical and immunoblot analyses demonstrated reduced cell surface expression of A590T. These findings suggest that the A590 residue plays an important role in the maintenance of channel surface expression and function (Kinoshita et al., 2014). Furthermore, pathogenic and likely pathogenic missense variants in nearby residues (T587M, T587R, G589D, R591C, R591H, R594P, R594Q) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, A590T in the KCNQ1 gene is interpreted as a likely pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000182224 SCV001148160 likely pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001027732 SCV001190323 likely pathogenic Long QT syndrome 1 2019-11-15 criteria provided, single submitter research
Color Health, Inc RCV001185983 SCV001352303 uncertain significance Arrhythmia 2018-12-11 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057634 SCV000089153 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:14998624;PMID:15840476;PMID:16623272;PMID:17329209;PMID:19841300;PMID:17329207). 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 RCV000223805 SCV000280150 uncertain significance not specified 2013-11-13 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.Ala590Thr Based on the data reviewed below we consider it a variant of uncertain significance, likely disease causing. The variant has been seen in one case of long QT, another case of possible neonatal long QT, and one case of drug-induced long QT. There is no segregation data available. Lupoglazoff et al (2004) first reported this variant in their French cohort. They observed it in a neonate with long QT syndrome. The patient was a male who presented with neonatal bradycardia and a QTc of 460 ms. At follow-up at 6 years of age he was asymptomatic. They note that the variant was inherited from the mother but no phenotypic data on the mother is provided. I had our peds EP team review this case and they felt the data reported was perhaps suspicious for a diagnosis of long QT but did not strongly support it. Couderc et al (2012) included a patient with this variant in an analysis of QT-RR relationship in patients with long QT, however the data for that study was pulled from a French database so this may be the same case that was reported by Lupoglazoff et all (2004). The variant was also reported in a compendium of variants found in Dr. Ackerman's research lab (Tester et al 2005). The variant was observed in 1 of 541 individuals with "suspected" long QT syndrome enrolled in Dr. Ackerman's studies. Individual phenotypic data was not reported, however sufficient data was available to calculate a Schwartz score in 77% of cases. A Schwartz score ? 4 (indicating high confidence in the diagnosis) was present 29% of the overall cohort and 40% of individuals with a KCNQ1 variant. The overall yield was 50%, compared to 70% in studies where all the patients had a firmer diagnosis of long QT syndrome. Taken together these data suggest that a proportion of patients in this study did not in fact have long QT syndrome. However, the same group later included a case with this variant in two other publications and noted that only cases with a strong diagnosis (Schwartz score ? 4 or QTc ? 480 ms were included) (Kapa et al 2009, Giudicessi et al 2012). Given ascertainment methods for the three papers it is likely they are all referring to the same case. I suspect this case was also included in a paper by Goldenberg et al (2011) and one by Barsheshet et al (2012) as Dr. Ackerman is a co-author on both and cases from his cohort were included. Goldenberg et al (2011) list three individuals with p.Ala590Thr, however the study included people with long QT and genotype-positive, phenotype-negative relatives, and it is unclear whether those three individuals had phenotype. Novotny et al (2006) reported the variant in a study on drug-induced long QT, though unfortunately the paper is in Czech. Using google translate it looks like they observed the variant in male with a QTc of 450 ms while on venlafixine (Effexor). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The alanine at codon 590 is conserved across mammals but is a serine in fugu and c elegans. Other variants have been reported in association with disease at nearby codons (p.Thr587Met, p.Gly589Asp, p.Arg591Cys, p.Arg591His, p.Arg594Gln, p.Arg594Pro, p.Glu596Lys). In total the variant has not been seen in ~8100 published controls and individuals from publicly available population datasets. There is no variation at codon 590 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6500 Caucasian and African American individuals (as of February 27th, 2013). The variant is in 1000 genomes and dbSNP (rs199472813) but only in reference to the reports with long QT syndrome.The variant was not observed in the following published control samples: 100 reportedly healthy individuals analyzed by Lupoglazoff et al (2004), 1500 presumed healthy individuals analyzed by Kapa et al (2009).

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