ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1751G>A (p.Gly584Glu) (rs199473009)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181891 SCV000234194 pathogenic not provided 2015-03-12 criteria provided, single submitter clinical testing p.Gly924Glu (GGG>GAG): c.2771 G>A in exon 12 of the KCNH2 (aka HERG) gene (NM_000238.2)The Gly924Glu mutation in the KCNH2 gene has been reported in one patient with LQTS and it was absent from 2,600 reference alleles (Kapplinger J et al., 2009). Additionally, the NHLBI ESP Exome Variant Server reports Gly924Glu was not observed in approximately 3,700 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Gly924Glu results in a non-conservative amino acid substitution of a non-polar Glycine with a negatively charged Glutamic acid. Mutations at this residue (Gly924Ala) and in nearby residues (Arg922Trp, Arg922Gln, Gly925Arg) have been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein.In summary, Gly924Glu in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in POSTMORTEM panel(s).
Ambry Genetics RCV000251484 SCV000319532 uncertain significance Cardiovascular phenotype 2016-07-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000817376 SCV000957931 uncertain significance Long QT syndrome 2018-08-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 924 of the KCNH2 protein (p.Gly924Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. While this variant is present in population databases (rs199473009), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals affected with long QT syndrome (PMID: 23338923, 19716085). ClinVar contains an entry for this variant (Variation ID: 67437). 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"). A different missense substitution at this codon (p.Gly924Ala) has been reported in an individual affected with sudden unexpected death in epilepsy (SUDEP) (PMID: 26704558). 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 RCV000058163 SCV000089683 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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