Distinct rates of VUS reclassification are observed when subclassifying VUS by evidence level.

Purpose: Genetic testing commonly yields a plethora of variants of uncertain significance (VUS) that can lead to ongoing uncertainty for patients and their caregivers. While all VUS hold uncertainty, some VUS have more evidence in support of pathogenicity while others have more evidence of a benign role. Sharing these nuances can help guide the investment in follow-up clinical and research investigations and may, at times, influence medical decision-making despite appreciated uncertainty.

ClinGen recuration of hearing loss associated-genes demonstrates significant changes in gene-disease validity over time.

Purpose: The ClinGen Hearing Loss Gene Curation Expert Panel (GCEP) was assembled in 2016 and has since curated 174 gene-disease relationships (GDRs) using ClinGen's semi-quantitative framework. ClinGen mandates timely recuration of all GDRs classified as Disputed, Limited, Moderate, and Strong, every 2-3 years.

Methods: Thirty-five GDRs met the criteria for recuration within two years of original curation.

Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL.

Bi-allelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females, all with a de novo single-nucleotide variant within the start codon or the 5' UTR of GLUL that truncates 17 amino acids of the protein product, including its critical N-terminal degron sequence. This truncation results in a disorder of abnormal glutamine synthetase stability and manifests as a phenotype of severe developmental and epileptic encephalopathy.

Design and implementation of an action plan for justice, equity, diversity, and inclusion within the Clinical Genome Resource.

How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments dedicated to each. Active involvement of consortium leadership, buy-in from its members at all levels, and support from NIH program staff at pivotal stages were essential to the success of this effort.

GREGoR: Accelerating Genomics for Rare Diseases.

Rare diseases are collectively common, affecting approximately one in twenty individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in DNA sequencing, development of new computational and experimental approaches to prioritize genes and genetic variants, and increased global exchange of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis.