ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1751G>C (p.Gly584Ala) (rs199473009)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000454684 SCV000539441 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband.
Invitae RCV000468983 SCV000543457 uncertain significance Long QT syndrome 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 924 of the KCNH2 protein (p.Gly924Ala). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and alanine. While this variant is not present in population databases (rs199473009), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. ClinVar contains an entry for this variant (Variation ID: 67438). This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085) and one individual with epilepsy (PMID: 26704558). 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. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000619828 SCV000735945 uncertain significance Cardiovascular phenotype 2017-07-20 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 RCV000058164 SCV000089684 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). 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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