ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1733A>C (p.His578Pro) (rs794728376)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181814 SCV000234117 uncertain significance not provided 2014-05-10 criteria provided, single submitter clinical testing p.His578Pro (CAC>CCC): c.1733 A>C in exon 7 of the KCNH2 gene (NM_000238.2)A variant of unknown significance has been identified in the KCNH2 gene. The H578P variant in the KCNH2 gene results in minimal impairment of channel function (Jiang M et al., 1999). Additionally, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Nevertheless, the H578P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Moreover, the H578P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, missense mutations in nearby residues (M574V, E575G, M579T, R582C) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in LQT panel(s).

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