Disease-specific ACMG/AMP guidelines improve sequence variant interpretation for hearing loss
Disease-specific ACMG/AMP guidelines improve sequence variant interpretation for hearing loss
Abstract PurposeThe ClinGen Variant Curation Expert Panels (VCEPS) provide disease-specific rules for accurate variant interpretation. Using hearing loss-specific American College of Medical Genetics/Association for Molecular Pathology (HL-specific ACMG/AMP) guidelines, the ClinGen Hearing Loss VCEP (HL VCEP) illustrates the utility of expert specifications in resolving conflicting variant interpretations. MethodsA total of 157 variants across nine hearing loss genes were curated and submitted to ClinVar by the HL VCEP. The curation process consisted of collecting published and unpublished data for each variant by biocurators, followed by bi-monthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific ACMG/AMP guidelines to reach a final classification. ResultsBefore expert curation, 75% (117/157) of variants had single or multiple VUS submissions (17/157) or had conflicting interpretations in ClinVar (100/157). After applying the HL-specific ACMG/AMP guidelines, 24% (4/17) of VUS variants and 69% (69/100) of discordant variants were resolved into Benign (B), Likely Benign (LB), Likely Pathogenic (LP), or Pathogenic (P). Overall, 70% (109/157) variants had unambiguous classifications (B, LB, LP, P). We quantify the contribution of the HL-specified ACMG/AMP codes to variant interpretation. ConclusionExpert specification and application of the HL-specific ACMG/AMP guidelines effectively resolved discordant interpretations in ClinVar. This study supports the utility of ClinGen VCEPs in helping the community move towards more consistent variant interpretations, which will improve the care of patients with genetic disorders.
Hughes Madeline Y、Kenna Margaret、Azaiez Hela、Booth Kevin T、Avraham Karen B、Amr Sami S、Oza Andrea M、Hemphill Sarah E、Shen Jun、Schimmenti Lisa A、Nara Kiyomitsu、Patel Mayher J、Grant Andrew R、Boczek Nicole J、Kremer Hannie、Siegert Rebecca K、Cushman Brandon J、Rehm Heidi L、ClinGen Hearing Loss Clinical Domain Working Group、Abou Tayoun Ahmad N、Wilcox Emma H、Chapin Alex、DiStefano Marina T、Griffith Andrew
The Broad Institute of MIT and HarvardDept. of Otolaryngology and Communication Enhancement, Boston Children?ˉs Hospital||Harvard Medical SchoolMolecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa Hospital and ClinicsMolecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa Hospital and Clinics||Department of Neurobiology, Harvard Medical SchoolDepartment of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv UniversityLaboratory for Molecular Medicine, Mass General Brigham Personalized Medicine||Harvard Medical SchoolLaboratory for Molecular Medicine, Mass General Brigham Personalized Medicine||Dept. of Otolaryngology and Communication Enhancement, Boston Children?ˉs HospitalLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineLaboratory for Molecular Medicine, Mass General Brigham Personalized Medicine||Harvard Medical SchoolDepartment of Otorhinolaryngology, Clinical Genomics and Biochemistry and Molecular BiologyDivision of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical CenterThe Broad Institute of MIT and HarvardThe Broad Institute of MIT and HarvardDept of Laboratory Medicine & PathologyDepartment of Human Genetics, Radboud University Medical CenterThe Broad Institute of MIT and HarvardLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineThe Broad Institute of MIT and Harvard||Laboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAl Genomics Center, Al Jalila Children?ˉs Specialty Hospital||Center for Genomic Discovery, Mohammed Bin Rashid University of Medicine and Health SciencesThe Broad Institute of MIT and HarvardARUP LaboratoriesThe Broad Institute of MIT and Harvard||Precision Health ProgramDepartment of Otolaryngology Head-Neck Surgery, College of Medicine, The University of Tennessee Health Science Center
耳鼻咽喉科学遗传学医学研究方法
Hughes Madeline Y,Kenna Margaret,Azaiez Hela,Booth Kevin T,Avraham Karen B,Amr Sami S,Oza Andrea M,Hemphill Sarah E,Shen Jun,Schimmenti Lisa A,Nara Kiyomitsu,Patel Mayher J,Grant Andrew R,Boczek Nicole J,Kremer Hannie,Siegert Rebecca K,Cushman Brandon J,Rehm Heidi L,ClinGen Hearing Loss Clinical Domain Working Group,Abou Tayoun Ahmad N,Wilcox Emma H,Chapin Alex,DiStefano Marina T,Griffith Andrew.Disease-specific ACMG/AMP guidelines improve sequence variant interpretation for hearing loss[EB/OL].(2025-03-28)[2025-08-02].https://www.medrxiv.org/content/10.1101/2021.01.27.21250652.点此复制
评论