ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1969G>A (p.Gly657Ser) (rs199472978)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205745 SCV000261846 pathogenic Long QT syndrome 2017-05-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 657 of the KCNH2 protein (p.Gly657Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085). and had been seen in individuals affected with long QT (Invitae database). ClinVar contains an entry for this variant (Variation ID: 67348) This variant identified in the KCNH2 gene is located in the transmembrane spanning S5/pore region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. Experimental studies have shown that this missense change affects the inactivation of the channel (PMID: 26958806, 17823114). A different variant affecting this nucleotide (c.1969G>T, p.Gly657Cys) has been determined to be pathogenic (PMID: 18752142, 26675252, 19862833, 18955593). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. In summary, this variant has been reported in affected individuals and shown to have a deleterious effect on protein function. It also affects a residue previously known to be important for protein function. For these reasons it has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058068 SCV000089588 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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