ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.982C>T (p.Arg328Cys) (rs199473505)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157262 SCV000206992 likely benign not specified 2015-11-10 criteria provided, single submitter clinical testing
GeneDx RCV000157262 SCV000234077 uncertain significance not specified 2017-03-08 criteria provided, single submitter clinical testing The R328C variant in the KCNH2 gene has been previously reported in multiple unrelated individuals with LQTS and was absent in >2,600 reference alleles, when considering all published studies (Tisma-Dupanovic et al., 2013; Kapplinger et al., 2009; Tester et al., 2005; Chevalier et al., 2001). The R328C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; however, the 1000 Genomes Project observed this variant at low frequency in 2/198 Finnish alleles and in 2/208 Puerto Rican alleles. One previously asymptomatic individual identified to have the R328C variant developed Torsades de Pointes in the context of respiratory distress, left ventricular dysfunction, and a prolonged QT interval while being treated with multiple medications (Hinterseer et al., 2006). Several relatives who were also found to harbor this variant, including the patient's identical twin, had no clinical evidence of LQTS, leading authors to conclude this patient's arrhythmia likely resulted from multiple factors. Chevalier et al. (2001) reported R328C leads to a partial dominant-negative effect and alters KCNH2 channel function; however, subsequent functional studies found that the channel function of R328C-KCNH2 did not differ significantly from the wild type KCNH2 channel function (Grunnet et al., 2005; Anderson et al., 2006). Nevertheless, R328C is a non-conservative amino acid substitution occurring at a position that is conserved across species. Multiple missense variants in nearby residues (S320W, S320L, D323N, P334L) have been reported in Human Genome Mutation Database in association with LQTS (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
CSER_CC_NCGL; University of Washington Medical Center RCV000210884 SCV000264604 likely benign Long QT syndrome 2015-12-01 criteria provided, single submitter research
Invitae RCV000210884 SCV000283991 benign Long QT syndrome 2017-12-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620416 SCV000737614 uncertain significance Cardiovascular phenotype 2016-07-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058281 SCV000089801 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:11334843;PMID:14760488;PMID:15840476;PMID:16253915;PMID:16432067;PMID:16720674;PMID:16922724;PMID:17275752;PMID:19716085;PMID:19841300).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000058281 SCV000280132 likely benign not provided 2016-11-15 no assertion criteria provided provider interpretation Given the weak case data and presence in population controls, we consider this variant likely benign. One possibility is that this variant contributes to an arrhythmic phenotype, perhaps behaving as a modifier, but not be the primary driver. This is based on the fact that several of the reported cases involved either a more convincing pathogenic variant or QT-prolonging medication, several other reported cases are from cohorts that include individuals who do not have long QT, and the variant is present in individuals not selected for a long QT phenotype, with ~1% of one such cohort having the variant. This is a previously reported variant in the N-terminal region. To date, the reported cases include - drug-induced long QT, complete AV block and Torsades: 2 - patients referred for long QT genetic testing, 25-50% likely don't have long QT: 6 - patients with long QT, all major genes analyzed with no other variants: 4 - patients with long QT and another, high confidence variant: 1 - patient with prolonged QT in the setting of evidence of arrhythmogenic right ventricular cardiomyopathy and a PKP2 frameshift variant: 1 Comparing frequencies: - 4/2500 in Kapplinger series (0.16%) - 64/60,618 in ExAC (0.11%) - 38/3189 Finnish in ExAC (1.2%) -162/141,162 in gnomAD (0.11%); -115/13031 Finnish in gnomAD (0.88%) Chevalier et al (2001) reported the variant in association with what the authors described as acquired long QT syndrome. They found the variant in 1 of 16 cases. The individual with the variant was a 45yo male with no prior medical history of family history of sudden death. He was hospitalized for recent syncopal episodes. An ECG at admission showed QT prolongation and complete AV block, he was diagnosed with "Torsades de pointes" complicating an AV bock and a pacemaker was placed and the QT interval returned to normal once he was paced. Tester et al (2005) observed the variant in 2 of 541 cases. This publication is a compendium of variants identified in cases referred to Dr. Ackerman's research lab for long QT genetic testing. No individual clinical or segregation data was provided. Of note when considering this paper, it is likely that ~25% of patients in this cohort did not actually have long QT syndrome (based on the reported yield). Millat et al (2006) reported the variant in 3 of 44 unrelated individuals from their French cohort with long QT syndrome with QTc intervals ranging from 483 to 540 ms. No segregation data was provided. They analyzed 5 long QT genes. Hinterseer et al (2006) reported the variant in a 25yo woman who suffered Torsades de Pointes in the setting of transiently impaired LV function, acute respiratory distress syndrome, transient hypokalaemia and QT-prolonging drugs, with a QTc of 485-510 ms. Once her status had normalized and QT-prolonging drugs had been discontinued her QTc was 430 ms and a Dl-sotalol challenge evoked a QTc of 515 ms, which the authors felt was suggestive of a latent susceptibility to QT-prolonging drugs. Four other family members were found to have the variant, "all without clinical manifestations of LQTS". The variant was reported in 4 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). Stattin et al (2012) analyzed 5 long QT genes in 200 unrelated long QT patients from their Swedish cohort and identified this variant in one individual. Hedley et al (2013) reported on sequencing of five long QT genes in 44 South African patients with long QT syndrome. One patient carried was a double heterozygote for a founder variant, KCNQ1:p.A341V, and this variant, KCNH2:p.R328C. They did not provide any details about the patient's phenotype or segregation in the family. Tisma-Dupanovic et al (2013) reported a 14yo male who had a QTc of 497 ms as well as two major and two minor criteria for arrhythmogenic right ventricular cardiomyopathy (nonsustained ventricular tachycardia of LBBB morphology with a superior axis, MRI findings of regional right ventricular dyskinesia and ejection fraction less than 35%, inverted T waves in lead V1 and V2 and filtered QRS >114 ms on signal-averaged ECG). Genetic testing identified p.Arg328Cys in KCNH2. a frameshift in PKP2, and a missense in DSC2. Functional studies on the variant have reported conflicting results. Chevalier et al (2001) studied the functional impact of the variant on whole-cell current using patch-clamp measurements in transfected COS-7 cells and observed a reduced voltage-activated K current. Grunnet et al (2005) studied a family with this variant and a KCNQ1 variant (p.Arg591His). The KCNH2 variant showed no functional phenotype when studied in xenopus oocytes using two-electrode voltage clamp and by confocal imaging. Review of the pedigree reveals that one individual had both variants and had a QTc of 500 ms, two individuals had just the KCNQ1 variant had QTc of 499 ms and 460 ms, and one individual had just the KCNH2 variant with a QTc of 440 ms and t-wave-related abnormalities of repolarization on exercise and T-wave inversion in leads in V1-V3 on ECG. Ackerman’s group subsequently published functional characterization of several KCNH2 variants, including p.Arg328Cys (Anderson et al 2006). They too found no evidence of functional impact and suggested that this may be a rare benign variant. The Arginine at 328 is not uniformly conserved across species. The variant was reported online in 161 of 141,162 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The highest frequency was 115 of 13,031 Finnish individuals (0.88%). The variant was not observed in the following published control samples :200 individuals studied by Grunnet et al (2005), 1300 individuals reported by Kapplinger et al (2009, redundant with Tester et al 2005), 50 individuals reported by Chevalier et al (2001), 100 individuals reported by Millat et al (2006).

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