ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.215C>G (p.Pro72Arg) (rs199473421)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464288 SCV000543448 uncertain significance Long QT syndrome 2016-09-26 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 72 of the KCNH2 protein (p.Pro72Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in one individual affected with long QT syndrome (PMID: 23158531). ClinVar contains an entry for this variant (Variation ID: 67369). 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. A different missense substitution at this codon (p.Pro72Gln) has been determined to be pathogenic (PMID: 11854117, 25417810). This suggests that the proline residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. 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 is a rare missense change that has been reported in an affected individual and it affects an important functional residue. However, the available evidence is not sufficient at this point and further genetic and/or functional data is needed. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058089 SCV000089609 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:20960616). 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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