ArticleAmerican journal of medical genetics. Part A2022
Systematic use of phenotype evidence in clinical genetic testing reduces the frequency of variants of uncertain significance.
Article in American journal of medical genetics. Part A, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
16 citing papers in PubMed.
- Comprehensive evaluation of ACMG/AMP-based variant classification tools.Bioinformatics (Oxford, England) · 2026Article
- Exploring the strengths and limitations of AI-driven variant prioritization versus manual curation in inborn errors of immunity.Frontiers in genetics · 2026Article
- Investigating the frequency of unreported cases and laboratory correspondence practices for variants of uncertain significance in pediatric epilepsy.Epilepsia open · 2025Article
- Characterization of Variants of Uncertain Significance in ACADVL Gene From a Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency Patient.Molecular genetics & genomic medicine · 2025Article
- Harnessing genotype and phenotype data for population-scale variant classification using large language models and bayesian inference.Human genetics · 2025Article
- Molecular investigation in individuals with orofacial clefts and microphthalmia-anophthalmia-coloboma spectrum.European journal of human genetics : EJHG · 2024Article
- Reclassification of Variants Following Renal Genetics Testing: Uncommon Yet Impactful for Diagnosis and Management.Kidney international reports · 2024Article
- Navigating the landscape of clinical genetic testing: insights and challenges in rare disease diagnostics.Childhood kidney diseases · 2024Review
- Advancing precision medicine through the integration of clinical cardiovascular genetics - An Asian perspective.Genetics in medicine open · 2024Article
- Rates and Classification of Variants of Uncertain Significance in Hereditary Disease Genetic Testing.JAMA network open · 2023Article
- Beyond the exome: What's next in diagnostic testing for Mendelian conditions.American journal of human genetics · 2023Review
- The future role of facial image analysis in ACMG classification guidelines.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2023Article
- De novo ADGRV1 variant in a patient with ictal asystole provides novel clues for increased risk of SUDEP.Acta epileptologica · 2023Article
- Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals.American journal of human genetics · 2023Article
- Article
- Systematic use of phenotype evidence in clinical genetic testing reduces the frequency of variants of uncertain significance.American journal of medical genetics. Part A · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Guidelines for variant interpretation include criteria for incorporating phenotype evidence, but this evidence is inconsistently applied. Systematic approaches to using phenotype evidence are needed. We developed a method for curating disease phenotypes as highly or moderately predictive of variant pathogenicity based on the frequency of their association with disease-causing variants. To evaluate this method's accuracy, we retrospectively reviewed variants with clinical classifications that had evolved from uncertain to definitive in genes associated with curated predictive phenotypes. To demonstrate the clinical validity and utility of this approach, we compared variant classifications determined with and without predictive phenotype evidence. The curation method was accurate for 93%-98% of eligible variants. Among variants interpreted using highly predictive phenotype evidence, the percentage classified as pathogenic or likely pathogenic was 80%, compared with 46%-54% had the evidence not been used. Positive results among individuals harboring variants with highly predictive phenotype-guided interpretations would have been missed in 25%-37% of diagnostic tests and 39%-50% of carrier screens had other approaches to phenotype evidence been used. In summary, predictive phenotype evidence associated with specific curated genes can be systematically incorporated into variant interpretation to reduce uncertainty and increase the clinical utility of genetic testing.
Indexed as
Identifiers
What OpenQuestion holds
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.