ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.2152G>A (p.Ala718Thr) (rs555269990)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000560315 SCV000627479 uncertain significance Long QT syndrome 2017-05-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1058 of the KCNH2 protein (p.Ala1058Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs555269990, ExAC 0.007%). This variant has not been reported in the literature in individuals with a KCNH2-related disease. 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on KCNH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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