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Background: Familial hypercholesterolemia (FH) is a genetically determined monogenic disorder of predominantly autosomal dominant inheritance. A number of studies on differences in the genetic profile of patients with FH have demonstrated the importance of a more substantive evaluation of genetic features. The aim of this study was to evaluate the genetic profile of patients with clinical FH among Italian and Russian patients., Methods: We included 144 Italian and 79 Russian FH patients; clinical diagnosis was based on the same criteria. Patients were divided in: positive to genetic test (one causative variant), inconclusive (only variants of uncertain clinical significance [VUS]), and negative (with likely benign/benign variants, heterozygous variants in LDLRAP1 gene, or without causative variants)., Results: The genetic test was positive in 76.4 % of the Italian patients and in 49.4 % of the Russian patients. The presence of VUS alone was detected in 7.6 % and in 19.0 % (p < 0.001), respectively. Among patients with positive genetic diagnosis, pre-treatment LDL-C levels were higher in the Russian cohort (353.5 ± 111.3 vs. 302.7 ± 52.1 mg/dL, p = 0.009), as well as the percentage of treated patients (53.8 % vs. 14.5 %, p < 0.001) and the prevalence of premature coronary heart disease (12.8 % vs. 3.6 %, p = 0.039). Among patients carrying only VUS, mean pre-treatment LDL-C levels were similar between the cohorts (299.5 ± 68.1 vs. 295.3 ± 46.8 mg/dL, p = 0.863). Among pathogenic/likely pathogenic variants and VUS, only 5 % and 4 % was shared between the two cohorts, respectively., Conclusion: The genetic background of patients clinically diagnosed with FH in two different countries is characterized by high variability., Competing Interests: Conflict of interest disclosures All authors declare no support from any organization for the submitted work; no other relationships or activities that could appear to have influenced the submitted work.| MG, OR, EU, VB, FP, FG, EO, MC and ADC report no conflict of interest disclosures. MA has received research grant support from Amryt Pharmaceutical, Amgen, IONIS, Akcea Therapeutics, Daiichi-Sankyo; Novartis, Pfizer, and Sanofi, has served as a consultant for Amgen, Akcea Therapeutics, Daiichi-Sankyo, Novartis, Pfizer, Sanofi, and Alfasigma, and has received lecturing fees from Amgen, Amryt Pharmaceutical, Daiichi-Sankyo, Regeneron, Sanofi, and Alfasigma. LDE received research funding and/or honoraria for advisory boards or speaker bureau from Amarin, Sobi, Novartis, Bayer, Aurora Biopharma, Amryt, and Daiichi-Sankyo. AA received research funding and/or honoraria for speaker bureau from Abbott, Amgen, AstraZeneca, Novartis, Pfizer, Recordati, Sanofi-Regeneron, Teva. ALC received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Mediolanum, Merck or MSD, Pfizer, Recordati, Rottapharm, Sanofi-Regeneron, Sigma-Tau., (Copyright © 2024 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)