ArticleAmerican journal of human genetics2024
ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification.
Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed.
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- Review
- A Tarui Disease Phenotype with Compensated Hemolysis and a HomozygousJournal of clinical medicine · 2026Article
- Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.Human genetics · 2026Article
- From Guidelines to Practice: Pilot Implementation and Analytical Boundaries of a Focused ADPKD-Spectrum Gene Panel.Diagnostics (Basel, Switzerland) · 2026Article
- BiallelicJournal of neuromuscular diseases · 2026Article
- Genetic testing in pituitary adenomas: a Pituitary Society International Consensus Statement.Nature reviews. Endocrinology · 2026Review
- Guidance for clinical variant classification in genes for spliceosomal small nuclear RNAs.medRxiv : the preprint server for health sciences · 2026Article
- Similarities and differences in the late-onset GM2 gangliosidoses: Tay-Sachs and Sandhoff diseases.Journal of neurology · 2026Article
- Neuropathy-predominant and hyperkinetic-dystonic presentations in two siblings with a homozygous VPS13A variant: long-term follow-up and family-based clinical analysis.BMC neurology · 2026Article
- Missense variants in KATNA1 alter microtubule dynamics and underlie dominant macular dystrophy.Research square · 2026Article
- The importance and clinical utility of reanalysis of exome and genome sequencing data.Kidney research and clinical practice · 2026Article
- Genetic spectrum and clinical features of PMP22 point mutations in Japanese Charcot-Marie-Tooth disease.Journal of neurology · 2026Article
- First Exonic Cryptic Branchpoint Variant in an Inherited Retinal Degeneration Detected in an IrishGenes · 2026Article
- Pontocerebellar hypoplasia type 9 with a novel combination of compound heterozygous variants in AMPD2.Human genome variation · 2026Article
- Charcot-Marie-Tooth disease type 1E: clinical natural history and molecular impact of PMP22 variants.Brain : a journal of neurology · 2026Article
- Reporting a Novel Disease Causing Variant in PGAP3 Associated With Hyperphosphatasia and Intellectual Disability: A Case Report and Comprehensive Literature Review.Molecular genetics & genomic medicine · 2026Review
- Comprehensive evaluation of ACMG/AMP-based variant classification tools.Bioinformatics (Oxford, England) · 2026Article
- Improving precision diagnosis in unexplained CKD.Clinical kidney journal · 2026Article
13 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors.
Funding
Abstract
The 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification publication established a standard employed internationally to guide laboratories in variant assessment. Those recommendations included both pathogenic (PP1) and benign (BS4) criteria for evaluating the inheritance patterns of variants, but details of how to apply those criteria at appropriate evidence levels were sparse. Several publications have since attempted to provide additional guidance, but anecdotally, this issue is still challenging. Additionally, it is not clear that those prior efforts fully distinguished disease-gene identification considerations from variant pathogenicity considerations nor did they address autosomal-recessive and X-linked inheritance. Here, we have taken a mixed inductive and deductive approach to this problem using real diseases as examples. We have developed a practical heuristic for genetic co-segregation evidence and have also determined that the specific phenotype criterion (PP4) is inseparably coupled to the co-segregation criterion. We have also determined that negative evidence at one locus constitutes positive evidence for other loci for disorders with locus heterogeneity. Finally, we provide a points-based system for evaluating phenotype and co-segregation as evidence types to support or refute a locus and show how that can be integrated into the Bayesian framework now used for variant classification and consistent with the 2015 guidelines.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.