ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1664C>T (p.Thr555Met) (rs199473434)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000699702 SCV000828425 uncertain significance Long QT syndrome 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 895 of the KCNH2 protein (p.Thr895Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. 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 an individual affected with atrial fibrillation and in two relatives with paroxysmal palpitations (PMID: 26129877). In has been also reported in an infant that suffered sudden death by unknown causes (PMID: 18596570). ClinVar contains an entry for this variant (Variation ID: 67426). This variant identified in the KCNH2 gene is located in the cytoplasmic C-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. Two experimental studies have shown that this missense change delays the deactivation of the KCNH2 channel (PMID: 18596570, 26129877). However, while one of the studies reports a decrease in the channel current, the other study reports an increase. The functional significance of these findings is uncertain. 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058151 SCV000089671 not provided SUDDEN INFANT DEATH SYNDROME no assertion provided literature only This variant has been reported as associated with Sudden infant death syndrome in the following publications (PMID:18596570). 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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