Purpose: The ClinGen Variant Curation Expert Panels (VCEPs) provide disease-specific rules for accurate variant interpretation. Using the hearing loss-specific ACMG/AMP guidelines, the Hearing Loss VCEP (HL VCEP) illustrates the utility of expert specifications in variant interpretation. Methods: A total of 157 variants across nine HL genes, previously submitted to ClinVar, were curated by the HL VCEP. The curation process involved collecting published and unpublished data for each variant by biocurators, followed by bi-monthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific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. Results: Before 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 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 classification. Conclusion: Expert specification and application of the HL-specific ACMG/AMP guidelines effectively resolved discordant interpretations in ClinVar. This study highlights the utility of ClinGen VCEPs in supporting more consistent clinical variant interpretation.
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 The curation process consisted of collecting published and unpublished data for each variant by biocurators, followed by bi-monthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific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.
Background: Hearing loss (HL) is the most common sensory deficit from birth, with at least 50 % due to an underlying genetic etiology. A genetic evaluation is a recommended component to the medical workup for HL, and a genetic diagnosis can impact medical management and provide prognostic and recurrence risk information. The accuracy of a genetic diagnosis relies on the evidence supporting the gene–disease relationship, as well as the evidence supporting individual variant classifications. As such, the ClinGen Hearing Loss Working Group was formed and tasked with curating genes associated with genetic hearing loss and developing specifications of the ACMG/AMP variant interpretation guidelines with the goal of improving the genetic diagnosis of patients with HL. Objectives: To describe the prioritization and expert curation of genes and variants associated with HL performed under the purview of the ClinGen Hearing Loss Gene and Variant Expert Panels (HL GCEP and VCEP). Materials and methods: HL genes were taken from clinical testing panels in the Genetic Testing Registry and prioritized based on a nonsyndromic presentation. Variants were taken from ClinVar and those with diverse data types and medically significant conflicts were prioritized to test the specified variant interpretation guidelines and to resolve classification discrepancies, respectively. Conclusions: The ClinGen HL GCEP has curated 174 gene–disease pairs. The HL VCEP has submitted 77 variants, including the previously controversial p.Met34Thr and p.Val37Ile variants in GJB2, into ClinVar, as an FDA-recognized database. Collaboration across clinics and laboratories were crucial to these curations and highlight the impact that data sharing can have on patient care.
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