ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.526C>T (p.Arg176Trp) (rs36210422)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157257 SCV000206987 risk factor Long QT syndrome 2 2015-09-24 criteria provided, single submitter clinical testing
GeneDx RCV000058238 SCV000234064 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing The R176W variant has been reported multiple times in association with LQTS, but also has been considered a benign variant due to its occurrence in presumably healthy Caucasian individuals. Initially, R176W was found to segregate with LQTS in one Finnish family, while it was absent from 240 control alleles (Lahtinen et al., 2000). Later, Fodstad et al. (2004) reported R176W as one of four Finnish founder mutations associated with LQTS, with a prevalence of 8%. Up to 2006, R176W was identified in a total of 92 individuals from 16 Finnish LQTS families. Of those, 6 individuals from 4 LQTS families were also heterozygous for another known pathogenic variant in KCNQ1. ECG data from 62 individuals heterozygous for R176W and 65 individuals without this change showed a significant prolongation of the QTc interval in those who tested positive for R176W, and 35% of the 92 individuals with R176W were symptomatic (eg., syncope, sudden cardiac arrest) (Fodstad et al., 2006). Nevertheless, R176W was also identified in 3/317 (0.9%) randomly collected adult Finnish blood donors (Fodstad et al., 2006) and, based on a large population study, 1 in 400 Finnish individuals over the age of 30 years were found to harbor R176W (16/6263 individuals studied). While these 16 individuals were asymptomatic, their QTc intervals showed a modest prolongation by 22.2ms (+/-4.7).In the Finnish studies, R176W has been regarded as a pathogenic variant associated with LQTS that has a milder phenotype, shows clinical variability, and has a low penetrance ranging from 23%-35% (Fodstad et al., 2004, 2006; Marjamaa et al., 2009). According to Marjamaa et al. (2009), individuals who are heterozygous for R176W are considered to be at increased risk for arrhythmia especially due to exposure to QT-prolonging medication, ischemia, structural heart disease, or other factors.Outside of Finland, R176W has been reported in a Caucasian child with LQTS and torsades de pointes tachycardia (Donner et al., 2012). R176W has also been observed in >30 unrelated individuals referred for LQTS testing at GeneDx, at least 5 of whom also had another pathogenic/likely pathogenic variant in KCNH2 or KCNE1. Although R176W was identified in presumed healthy Caucasian controls, with the minor allele frequency ranging from 0.5% (1/187 individuals) to 1.1% (1/46 individuals; rs36210422), it was absent in other populations tested, including 307 African-American and 134 Asian individuals (Ackerman et al., 2003). Additionally, recent data from the Genome Aggregation Database have shown that this variant is found in 10/8044 (0.12%) alleles from individuals of European (Finnish) ancestry and 31/44062 (0.07%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Electrophysiological in vitro studies of R176W demonstrated changes of HERG channel function, such as reduction in current density and tail current, and slightly altered deactivation kinetics. However a dominant-negative effect as observed for other pathogenic KCNH2 variants was not present (Fodstad et al., 2006). A study using two induced pluripotent stem cell lines from an asymptomatic individual with R176W and a family history of sudden death in first-degree relatives also suggested a possible pathogenic effect of R176W.Electrophysiological studies of beating myocytes showed functional abnormalities consistent with LQTS, such as prolonged repolarization time and increased arrhythmogenicity characteristics. However, results were not directly compared to those for known pathogenic LQTS variants, and other genetic factors could have contributed to the cellular phenotype (Lathi et al., 2012). Additionally, in a study by Jou et al. (2013), over-expression of this variant in KCNH2 knockout zebrafish rescued the phenotype and was classified as a benign variant. This assay correctly identified a benign variant in 9 of 10 cases and a disease-causing variant in 39/39 cases (Jou et al., 2013).In summary, R176W in the KCNH2 gene has been reported in association with LQTS with an incomplete penetrance ranging from 23% to 35% in the Finnish population. Since R176W has also been identified at a low frequency in asymptomatic individuals, we cannot exclude the possibility that the R176W variant may be a disease-modifying variant in the context of other pathogenic variants, genetic or environment factors, or a rare benign variant.
Invitae RCV000199086 SCV000253125 likely benign Long QT syndrome 2017-12-26 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000181761 SCV000539435 uncertain significance not specified 2017-02-03 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 8 papers, in affected and unaffected individuals, with some suggesting benign, others pathogenic and one calling it a Finnish founder mutation. It is classified in ClinVar with 1 star as Likely benign by Invitae, VUS by GeneDx and risk factor by Blueprint genomics. It is not present in ExAC but has a max MAF in gnomAD of 0.12% (10/8048 Finnish alleles and 33 european alleles). Note from April 2016: This variant has not undergone full assessment. The following are preliminary notes: conflicting reports. Also very difficult to do the full NVA because most papers we do not have access at. Possibly upgrade to VUS4? OB 12/28/15: VUS4 based on the full NVA. Heidi agrees that it is VUS4 and does not meet criteria for reporting.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000058238 SCV000609283 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000058238 SCV000696033 uncertain significance not provided 2016-04-26 criteria provided, single submitter clinical testing Variant summary: The c.526C>T variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a pathogenic outcome. While absent from the large population control database ExaC, the variant is reported in various control patients in the literature at a frequency of 0.3% and 0.10%, respectively (Ackerman_2003, Kapa_2009). This frequency exceeds the maximum expected allele frequency for a pathogenic KCNH2 variant of (0.01%), suggesting this is a benign polymorphism. The variant was originally reported to co-segregate in an affected family (Swan_1999), however after that publication the variant has been reported in both cases and control in the literature, and has conflicting views on pathogenicity via publications and clinical labs/databases. The variant was shown to be associated with a 22 ms prolongation of the age-, sex-, and heart rate-adjusted QT interval, supporting the role of the variant in predisposing to repolarization-related arrhythmogenesis, at least in the Finnish population (Marjamaa_2009). One functional study showed the variant to restore normal repolarization in the kcnh2-knockdown embryonic zebrafish (Jou_2013), suggesting the benign role of the variant. While the frequency of the variant in controls/healthy individuals along with the benign functional findings suggest this variant to be benign, the role as a risk factor cannot be ruled out. Therefore, this variant has been classified as VUS-Possibly Benign.
Ambry Genetics RCV000617719 SCV000737409 uncertain significance Cardiovascular phenotype 2018-01-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Conflicting evidence
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000199086 SCV000987628 risk factor Long QT syndrome criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058238 SCV000089758 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:10483966;PMID:10862094;PMID:14661677;PMID:16818214;PMID:17161064;PMID:19160088;PMID:19841300;PMID:19862833;PMID:16754261;PMID:22052944;PMID:22429796).
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000181761 SCV000804989 uncertain significance not specified 2015-11-10 no assertion criteria provided clinical testing

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