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Background: Missense variants in the MYH7 -encoded MYH7 (beta myosin heavy chain 7) represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7 -specific American College of Medical Genetics and Genomics (ACMG) variant classification guidelines were released recently but have yet to be assessed independently. We set out to assess the performance of the MYH7 -specific ACMG guidelines and determine if the addition of phenotype-enhanced criteria (PE-ACMG) using the HCM Genotype Predictor Score can further reduce the burden of variants of uncertain significance (VUS)., Methods: Re-assessment was performed on 70 MYH7 -variants in 121 unique patients from Mayo Clinic, and an independent cohort of 54 variants in 70 patients from Royal Prince Alfred Hospital (Australia). Qualifying variants were re-adjudicated using both standard ACMG and MYH7 -ACMG guidelines, and HCM Genotype Predictor Score was used to provide a validated measure of strength of clinical phenotype to be incorporated into the MYH7 -ACMG framework., Results: Among Mayo Clinic identified variants, 11/70 (16%) were classified as pathogenic (P), 10/70 (14%) as likely pathogenic, and 49/70 (70%) as a VUS. A similar distribution was seen in the Australian patients (12/54 [22%] P, 12/54 [22%] likely pathogenic, and 30/54 [56%] VUS; P =not significant). Application of the MYH7 -ACMG resulted in a nonsignificant reduction of the VUS burden in both cohorts from 49/70 to 39/70 (56%; P =0.1; Mayo Clinic) and from 30/54 to 20/54 (37%; P =0.1; Australia). Using the combined PE-MYH7-ACMG framework, the VUS decreased significantly from 49 to 27 ( P <0.001, Mayo Clinic) and from 30 to 16 ( P <0.001; Australia)., Conclusions: Use of the MYH7 -specific guidelines alone failed to significantly decrease VUS burden in 2 independent cohorts. However, a significant reduction in VUS burden was observed after the addition of phenotypic criteria. Using a patient's strength of sarcomeric HCM phenotype for variant adjudication can increase significantly the clinical utility of genetic testing for patients with HCM.