ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.2437C>T (p.His813Tyr) (rs199473035)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000691902 SCV000819701 uncertain significance Long QT syndrome 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 1153 of the KCNH2 protein (p.His1153Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs199473035, ExAC 0.04%). This variant has been observed in individuals affected with long QT syndrome (PMID: 16414944) and sudden unexplained death (PMID: 26164358). ClinVar contains an entry for this variant (Variation ID: 67497). 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: "Possibly Damaging"; 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.
Fulgent Genetics,Fulgent Genetics RCV000765941 SCV000897362 uncertain significance Short QT syndrome 1; Long QT syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000771779 SCV000904462 uncertain significance Arrhythmia 2018-10-30 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the 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 RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 16414944) and in an individual affected with sudden death (PMID: 26164358). This variant has also been identified in 12/232780 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058226 SCV000089746 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:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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