ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.235G>C (p.Ala79Pro) (rs794728494)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182052 SCV000234355 uncertain significance not provided 2017-12-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNH2 gene. The A79P variant has been reported previously in association with LQTS (Perry et al., 2016). The A79P variant is not observed in large population cohorts (Lek et al., 2016). The A79P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Perry et al. (2016) performed functional studies in Xenopus oocytes and demonstrated that A79P results in moderate perturbations to the Kv11.1 potassium channel response to premature stimuli that normalized when co-expressed with wild-type subunits, though the clinical relevance of this observation is uncertain. Missense variants in nearby residues (T74P, T74R, T74M, A78P) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Nevertheless, the A79P variant lacks observation in a significant number of affected individuals, segregation data, and additional functional evidence, which would further clarify its pathogenicity.

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