ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.2192A>C (p.His731Pro)

dbSNP: rs794728385
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181841 SCV000234144 likely pathogenic not provided 2014-01-31 criteria provided, single submitter clinical testing Tp.His731Pro (CAC>CCC): c.2192 A>C in exon 9 of the KCNH2 (HERG) gene (NM_000238.2)The H731P variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The H731P variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The H731 residue is conserved across species. In silico analysis predicts H731P is probably damaging to the protein structure/function. Mutations in nearby residues (P721L, I728F, S735L) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. Furthermore, the H731P 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.In summary, while H731P is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV002516847 SCV003440233 uncertain significance Long QT syndrome 2023-07-19 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 200417). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This missense change has been observed in individual(s) with long QT syndrome (PMID: 26669661; Invitae). This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 731 of the KCNH2 protein (p.His731Pro). This variant is not present in population databases (gnomAD no frequency).

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