ArticleGenetics in medicine : official journal of the American College of Medical Genetics2020
Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 2 of them syntheses that pooled it.
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Who cites it
30 citing papers in PubMed, 2 syntheses or guidelines pooled it, 44 citations in OpenAlex.
- Secondary findings in hereditary cancer genes after germline genetic testing - systematic review of literature.Human genetics · 2025Pooled it
- Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis.Open heart · 2022Pooled it
- Secondary findings after multi-gene panel testing in 7,388 patients with suspected cancer predisposition syndrome.Scientific reports · 2026Article
- SPINK1-related chronic pancreatitis: A model that encapsulates the spectrum of variant effects, genetic complexity, and classificatory challenges.American journal of human genetics · 2025Article
- Machine learning-based penetrance of genetic variants.Science (New York, N.Y.) · 2025Article
- Probability and Neurodegeneration: Alzheimer's Disease and Huntington's Disease.Brain sciences · 2025Article
- Using large-scale population-based data to improve disease risk assessment of clinical variants.Nature genetics · 2025Review
- Medically Actionable Secondary Findings from Whole-Exome Sequencing (WES) Data in a Sample of 3972 Individuals.International journal of molecular sciences · 2025Article
- Expanding the mutational spectrum of ReNU syndrome: insights into 5' Stem-loop variants.European journal of human genetics : EJHG · 2025Article
- A genotype-first approach identifies high incidence of NF1 pathogenic variants with distinct disease associations.Nature communications · 2025Article
- The Excess of Carriers in Rare Disorders Suggests a Nonpathogenic Effect for Most Variants of Uncertain Significance.Clinical genetics · 2025Article
- Meta-EA: a gene-specific combination of available computational tools for predicting missense variant effects.Nature communications · 2025Article
- Genetic Screening-Emerging Issues.Genes · 2024Review
- Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity.Genome medicine · 2023Article
- Prevalence of Monogenic Bone Disorders in a Dutch Cohort of Atypical Femur Fracture Patients.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2023Article
- Genetic Evaluation and Screening in Cardiomyopathies: Opportunities and Challenges for Personalized Medicine.Journal of personalized medicine · 2023Review
- Not putting the cart before the horse: the complex social and ethical terrain of prenatal exome sequencing.European journal of human genetics : EJHG · 2023Article
- Allelic prevalence and geographic distribution of cerebrotendinous xanthomatosis.Orphanet journal of rare diseases · 2023Article
- Utility of ACMG classification to support interpretation of molecular genetic test results in patients with factor VII deficiency.Frontiers in medicine · 2023Article
- Frequency of truncating FLCN variants and Birt-Hogg-Dubé-associated phenotypes in a health care system population.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeWe studied the penetrance of pathogenically classified variants in an elderly Dutch population from the Rotterdam Study, for which deep phenotyping is available. We screened the 59 actionable genes for which reporting of known pathogenic variants was recommended by the American College of Medical Genetics and Genomics (ACMG), and demonstrate that determining what constitutes a known pathogenic variant can be quite challenging.
methodsWe defined "known pathogenic" as classified pathogenic by both ClinVar and the Human Gene Mutation Database (HGMD). In 2628 individuals, we performed exome sequencing and identified known pathogenic variants. We investigated the clinical records of carriers and evaluated clinical events during 25 years of follow-up for evidence of variant pathogenicity.
resultsOf 3815 variants detected in the 59 ACMG genes, 17 variants were considered known pathogenic. For 14/17 variants the ClinVar classification had changed over time. Of 24 confirmed carriers of these variants, we observed at least one clinical event possibly caused by the variant in only three participants (13%).
conclusionWe show that the definition of "known pathogenic" is often unclear and should be approached carefully. Additionally variants marked as known pathogenic do not always have clinical impact on their carriers. Definition and classification of true (individual) expected pathogenic impact should be defined carefully.
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