ArticleThe Journal of molecular diagnostics : JMD2018
Curating Clinically Relevant Transcripts for the Interpretation of Sequence Variants.
Article in The Journal of molecular diagnostics : JMD, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Allostery is a widespread cause of loss-of-function variant pathogenicity.Nature communications · 2026Article
- TRACE: A Framework for Integrating Transcript Relevance Into ACMG/AMP Variant Interpretation.Human mutation · 2026Review
- Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data.American journal of human genetics · 2023Article
- Advanced variant classification framework reduces the false positive rate of predicted loss of function (pLoF) variants in population sequencing data.medRxiv : the preprint server for health sciences · 2023Article
- Analysis of autosomal dominant genes impacted by copy number loss in 24,844 fetuses without structural abnormalities.BMC genomics · 2022Article
- Internal Standardization of the Interpretation and Reporting of Sequence Variants in Hematologic Neoplasms.Molecular diagnosis & therapy · 2021Article
- The Impact of Modern Technologies on Molecular Diagnostic Success Rates, with a Focus on Inherited Retinal Dystrophy and Hearing Loss.International journal of molecular sciences · 2021Review
- Overview of PAX gene family: analysis of human tissue-specific variant expression and involvement in human disease.Human genetics · 2021Review
- TMPRSS3 Gene Variants With Implications for Auditory Treatment and Counseling.Frontiers in genetics · 2021Article
- Screening Consanguineous Families for Hearing Loss Using the MiamiOtoGenes Panel.Genetic testing and molecular biomarkers · 2020Article
- Clinical Interpretation of Sequence Variants.Current protocols in human genetics · 2020Article
- Increased diagnostic yield by reanalysis of data from a hearing loss gene panel.BMC medical genomics · 2019Article
- Pitfalls of clinical exome and gene panel testing: alternative transcripts.Genetics in medicine : official journal of the American College of Medical Genetics · 2019Article
- Systematic evaluation of gene variants linked to hearing loss based on allele frequency threshold and filtering allele frequency.Scientific reports · 2019Article
- Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.Human mutation · 2018Article
- Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.Human mutation · 2018Article
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
Variant interpretation depends on accurate annotations using biologically relevant transcripts. We have developed a systematic strategy for designating primary transcripts and have applied it to 109 hearing loss-associated genes that were divided into three categories. Category 1 genes (n = 38) had a single transcript; category 2 genes (n = 33) had multiple transcripts, but a single transcript was sufficient to represent all exons; and category 3 genes (n = 38) had multiple transcripts with unique exons. Transcripts were curated with respect to gene expression reported in the literature and the Genotype-Tissue Expression Project. In addition, high-frequency loss-of-function variants in the Genome Aggregation Database and disease-causing variants in ClinVar and the Human Gene Mutation Database across the 109 genes were queried. These data were used to classify exons as clinically significant, insignificant, or of uncertain significance. Interestingly, 6% of all exons, containing 124 reportedly disease-causing variants, were of uncertain significance. Finally, we used exon-level next-generation sequencing quality metrics generated at two clinical laboratories and identified a total of 43 technically challenging exons in 20 different genes that had inadequate coverage and/or homology issues that might lead to false-variant calls. We have demonstrated that transcript analysis plays a critical role in accurate clinical variant interpretation.
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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.