ArticleGenetics in medicine : official journal of the American College of Medical Genetics2017
Using high-resolution variant frequencies to empower clinical genome interpretation.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 279 papers, 2 of them syntheses that pooled it.
What it found
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Who cites it
279 citing papers in PubMed, 2 syntheses or guidelines pooled it, 459 citations in OpenAlex.
- A multiancestry polygenic risk score improves stratification in patients with hypertrophic cardiomyopathy.Nature cardiovascular research · 2026Pooled it
- Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.Genes · 2023Pooled it
- International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework.Circulation. Genomic and precision medicine · 2021Trial
- MultimodalCirculation · 2026Article
- Gene-specific reclassification patterns of variants in hypertrophic cardiomyopathy.European journal of human genetics : EJHG · 2026Article
- NovelJournal of clinical medicine · 2026Review
- Variant Site-Specific Natural History of Titin-Induced Cardiomyopathy: An International Multicenter Registry.Circulation. Genomic and precision medicine · 2026Article
- Population Reference Data in the Molecular Diagnosis of Pathogenic CAPN3 Variants: Contextual Evidence and Interpretive Limits.Molecular diagnosis & therapy · 2026Article
- Review
- Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.Human genetics · 2026Article
- Review
- 'Truthsets' for clinical validation of large-scale functional assays: Practice recommendations from Cancer Variant Interpretation Group UK (CanVIG-UK).medRxiv : the preprint server for health sciences · 2026Article
- Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy.Circulation · 2026Article
- An integrated, scaled approach to resolve TSC2 variants of uncertain significance.Nature communications · 2026Article
- AlphaMissense prediction for the evaluation of missense variants in the diagnostic setting of neuromuscular disorders.Journal of neuromuscular diseases · 2026Article
- Variant classification for mucopolysaccharidosis type I; ACMG/AMP specification for IDUA from the ClinGen lysosomal diseases variant curation expert panel.Molecular genetics and metabolism · 2026Article
- Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.Molecular medicine (Cambridge, Mass.) · 2026Article
- Ultra-rare variants in LAMA2 are risk factors for frontotemporal dementia and motor neuron disease.Human molecular genetics · 2026Article
- Specification of frequency criteria for secondary findings genes to improve variant classification concordance.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Molecular Analysis of miR-155 and MIR155HG Mutations in Conjunction with TLR4 Variants in Inflammatory Joint Disease.Current issues in molecular biology · 2026Article
219 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants.MethodsWe present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets.ResultsUsing the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false-positive rate<0.001).ConclusionWe outline a statistically robust framework for assessing whether a variant is "too common" to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.
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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.