ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1826A>C (p.Asp609Ala) (rs199472940)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000534743 SCV000627440 uncertain significance Long QT syndrome 2017-03-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 609 of the KCNH2 protein (p.Asp609Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is not present in population databases (ExAC no frequency) and 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 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 do not agree on the effect of this variant on channel function (PMID: 20133899, 19139152, 24725272). A different missense substitution at this codon (p.Asp609Gly) has been determined to be pathogenic (PMID: 15500450, 25417810). This suggests that the aspartic acid residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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