NM_000218.3(KCNQ1):c.565G>A (p.Gly189Arg) is a missense variant that causes replacement of glycine with arginine at position 189. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00002228, with 1/44884 in the East Asian population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). This variant is rare and has been reported in at least 2 apparently unrelated probands affected with long QT syndrome 1 (PS4_Supporting, PMID: 8528244, PMID: 10220144, PMID: 17470695). The computational predictor REVEL gives a score of 0.967, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.43 for donor loss, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP threshold of >0.5 and does not strongly predict that the variant disrupts the splicing of KCNQ1 (PP3). This variant has been shown to disrupt KCNQ1 function in three experimental assays, including manual patch-clamp, particularly in its impaired activation by treatment with the adenylyl cyclase / protein kinase A activator forskolin, and experimental / structural / functional simulation (PS3_Moderate; PMID: 22456477, PMID: 10376919, PMID: 29021305). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3_Moderate, PS4_Supporting, PM2_Supporting, and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025).