ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1928C>T (p.Thr643Ile) (rs149955375)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148532 SCV000050775 likely benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724866 SCV000225490 uncertain significance not provided 2015-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000724866 SCV000234204 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing p.Thr983Ile (ACT>ATT): c.2948 C>T in exon 12 of the KCNH2 (HERG) gene (NM_000238.2). The T983I mutation in the KCNH2 gene has been reported previously in one individual diagnosed with LQTS and it was absent from 1,488 control alleles from individuals of various ethnic backgrounds (Tester D et al., 2005). In addition, the T983I mutation was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. T983I results in 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. The T983 residue is conserved across species. In silico analysis predicts T983I is probably damaging to the protein structure/function. Furthermore, mutations in nearby residues in the C-terminus (P968L, N996I) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein . T983I also has been observed in three other unrelated individuals tested for LQTS at GeneDx.In summary, T983I in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Invitae RCV000148532 SCV000283979 uncertain significance Long QT syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 983 of the KCNH2 protein (p.Thr983Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs149955375, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in two individuals affected with long QT syndrome (LQTS) (PMID: 15840476, 23098067). ClinVar contains an entry for this variant (Variation ID: 67455). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000724866 SCV000885629 uncertain significance not provided 2018-05-04 criteria provided, single submitter clinical testing The KCNH2 c.2948C>T; p.Thr983Ile variant (rs149955375, ClinVar variant ID 67455) has been identified in at least three patients diagnosed with or referred for testing for long QT syndrome, but no family segregation data has been reported (Miszalski-Jamka 2017, Refsgaard 2012, Tester 2005). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.03% (identified on 32 out of 123,742 chromosomes). The threonine at position 983 is moderately conserved, considering 14 species, and computational analyses of the effects of the p.Thr983Ile variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Thr983Ile variant cannot be determined with certainty.
Color RCV000771359 SCV000903651 uncertain significance Arrhythmia 2018-05-01 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the C-terminal cytoplasmic domain of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals with Long QT syndrome (PMID 15840476, 23098067) and Short QT syndrome (PMID 23266818), but also in unaffected individuals (PMID 22378279 26746457). This variant is present in the general population (38/271860 chromosomes in the Genome Aggregation Database, gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000724866 SCV001155303 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058182 SCV000089702 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:15840476;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148532 SCV000190244 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000181901 SCV000280126 uncertain significance not specified 2014-12-03 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. KCNH2 p.Thr983Ile Given the weak case data and the presence in the general population, we consider this a variant of uncertain significance. We could find three reports of this variant that may be associated with phenotype, though unfortunately phenotypic details are either unavailable or unclear. Dr. Ackerman's group reported the variant in one of 541 patients referred to his lab for genetic testing for long QT syndrome. It is unclear if all of these patients had a diagnosis of long QT (Tester et al 2005). Individual phenotypic data is not provided. For the patients with a variant in KCNH2 identified the QTc was over 480 ms in 66% and the Schwartz score was >= 4 in 39%. Ancestry and segregation are not provided. I found two reports online, presumably from the same group, written in Russian, that appear to report this variant in a patient with short QT syndrome (http://www.defibrillation.ru/download/Annaly_aritmologii,2010,1,62-69.pdf and http://arrhythmology.pro/files/pdf/AA_04_2008_full.pdf). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar score 0.656). The threonine at codon 983 is conserved across species, as are neighboring amino acids. The only nearby variant I could find was p.Asn985Ser, which has reportedly been reported in association with Brugada syndrome. In total the variant has been seen in 4 of 7818 published controls and individuals from publicly available population datasets.The variant was reported online in 2 of 4297 Caucasian individuals and 1 of 2201 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of July 3rd, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). It is listed in dbSNP (rs149955375) with submissions from ESP/exome chip, ClinSeq (1 of 570 individuals(Ng et al 2013)), and a locus specific database. The variant was not observed in the following laboratory and published control samples: 750 control individuals (Tester et al 2005).

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