OBJECTIVES: Underrepresented minority (URM, comprising Hispanic, non-Hispanic Black, and Native American) children with sensorineural hearing loss have fivefold lower odds of receiving a genetic diagnosis after undergoing hearing loss gene-panel testing. Using hearing loss-specific American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines applied to a URM-specific cohort demonstrates the utility of these guidelines in reducing the disparity in diagnostic efficacy of genetic testing for URM populations. DESIGN: A total of 2740 variants from 715 patients with sensorineural hearing loss (1275 variants from 348 URM patients) were queried. ACMG variant interpretation guidelines with hearing loss expert specification were used to attempt reclassification of multihit (≥2 occurrences) variants of uncertain significances (VUSs), focusing on case-control analysis relative to ancestry-matched controls and computational prediction. RESULTS: Before curation, only 198 of the 1275 variants (15.52%) in the URM population were classified as likely pathogenic. Sixty-one multihit VUSs, including variants in OTOG, TJP2, COL11A2, and 34 other genes, were probed using hearing loss-specific ACMG/AMP guidelines, resulting in reclassification of 19 variants. For the remaining 42 VUSs, reclassification would require parental testing and segregation analysis. In addition to these VUSs that appeared at least twice in our dataset, many additional VUSs appeared only once, but were extremely rare or absent from ancestry-matched databases and could be reclassified with additional information. CONCLUSIONS: This study demonstrates the utility of the application of HL-specific ACMG/AMP classification to specifically URM variants and the dramatic effects it can have on clarifying pathogenicity of VUSs, thus contributing to clinicians' ability to improve the standard of care for URM patients with improved genetic testing accuracy and subsequent early intervention.