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The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin (VCL) gene illustrates these challenges. Model organism data provide evidence that loss of function of VCL may play a role in cardiomyopathy and aggregate case‐control studies suggest low penetrance. VCL loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with VCL loss‐of‐function variants and confirmed enrichment in probands with dilated cardiomyopathy (odds ratio [OR] = 9.01; confidence interval [CI] = 4.93–16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, VCL loss‐of‐function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance.

IntroductionOver the last 20 years, the Canadian province of Ontario implemented several new models of primary care focusing on changes to physician remuneration, clinics led by nurse practitioners and the introduction of interprofessional primary care teams. Health outcome and cost evaluations of these models thus far have been mostly cross-sectional and in some cases results from these studies were conflicting. The aim of this population-based study is to investigate short, medium and long-term effectiveness of these reforms over the past 15–20 years.Methods and analysisThis is the protocol for a retrospective cohort study including fee-for-service (FFS) and community health centre cohorts (control cohorts) or patients who switched from either being unattached or from FFS to a new practice model (eg, capitation, enhanced FFS, team, nurse practitioner-led) from 1997 to 2020. The primary outcome is total healthcare costs and secondary outcomes are primary care costs, other (non-primary care) health costs, hospitalisations, length of stay, emergency department visits, accessibility and mortality. A combination of hard and propensity matching will be used where relevant. Outcomes will be adjusted for demographic and health factors and measured annually. Interrupted time series models will be used where data permits and difference-in-differences methods will be used otherwise.Ethics and disseminationEthics approval has been received from Queens University and Memorial University. The dissemination plan includes conference presentations, papers, brief evidence summaries targeted at select audiences and knowledge brokering sessions with key stakeholders.

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