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Over 1000 hERG variants have been described by clinicians, but most remain to be characterised. The objective is to standardise and accelerate the phenotyping process to contribute to clinician diagnosis and patient counselling. <jats:italic>In silico<\/jats:italic> evaluation was also included to characterise the structural impact of the variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We selected 11 variants from known LQTS patients and two variants for which diagnosis was problematic. Using the Gibson assembly strategy, we efficiently introduced mutations in hERG cDNA despite GC\u2010rich sequences. A pH\u2010sensitive fluorescent tag was fused to hERG for efficient evaluation of channel trafficking. An optimised 35\u2010s patch\u2010clamp protocol was developed to evaluate hERG channel activity in transfected cells. R software was used to speed up analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the present work, we observed a good correlation between cell surface expression, assessed by the pH\u2010sensitive tag, and current densities. Also, we showed that the new biophysical protocol allows a significant gain of time in recording ion channel properties and provides extensive information on WT and variant channel biophysical parameters, that can all be recapitulated in a single parameter defined herein as the repolarisation power. The impacts of the variants on channel structure were also reported where structural information was available. These three readouts (trafficking, repolarisation power and structural impact) define three pathogenicity indexes that may help clinical diagnosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Fast\u2010track characterisation of <jats:italic>KCNH2<\/jats:italic> genetic variants shows its relevance to discriminate mutants that affect hERG channel activity from variants with undetectable effects. It also helped the diagnosis of two new variants. This information is meant to fill a patient database, as a basis for personalised medicine. The next steps will be to further accelerate the process using an automated patch\u2010clamp system.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.609","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T10:01:35Z","timestamp":1637661695000},"source":"Crossref","is-referenced-by-count":16,"title":["A standardised hERG phenotyping pipeline to evaluate <i>KCNH2<\/i> genetic variant pathogenicity"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2269-5750","authenticated-orcid":false,"given":"Barbara","family":"Oliveira\u2010Mendes","sequence":"first","affiliation":[{"name":"l'Institut du Thorax Inserm UMR 1087\/CNRS UMR 6291  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Feliciangeli","sequence":"additional","affiliation":[{"name":"Labex ICST, Universit\u00e9 C\u00f4te d'Azur, INSERM Centre National de la Recherche Scientifique, Institut de Pharmacologie 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