ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.491G>A (p.Arg164His) (rs199472866)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000202703 SCV000257648 uncertain significance Long QT syndrome 2 2015-07-01 criteria provided, single submitter clinical testing
Invitae RCV000473244 SCV000543472 uncertain significance Long QT syndrome 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 164 of the KCNH2 protein (p.Arg164His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals with long QT syndrome (22429796, Invitae), as well as individuals referred for long QT syndrome genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67508). This variant identified in the KCNH2 gene is located in the cytoplasmic N-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. It is unclear how this variant impacts the function of this protein. 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on KCNH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
SIB Swiss Institute of Bioinformatics RCV000202703 SCV000803450 uncertain significance Long QT syndrome 2 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Long QT syndrome 2, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058237 SCV000089757 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:19716085;PMID:22429796). 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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