Evidence map›Paper›PMID 42380775›Full record

ArticleBMC genomics2026

Variant-specific RNA testing resolves variants of uncertain significance in exome testing.

Audrey K O'Neill, Grace E VanNoy, Brooklynn Gasser, Jessica Gage, Jessica Grzybowski, Carolyn Horton, Melissa Holman, Claire Watson, Shoji Ichikawa, Changrui Xiao and 9 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in BMC genomics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

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.

2 · The registry

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.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors.

Audrey K O'NeillAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.
Grace E VanNoyAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA. gvannoy@ambrygen.com.
Brooklynn GasserAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.
Jessica GageAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.
Jessica GrzybowskiAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.
Carolyn HortonAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.
Melissa HolmanAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.
Claire WatsonAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.
Shoji IchikawaAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.
Changrui XiaoDepartment of Neurology, University of California Irvine Health, Orange, CA, USA.
Dana MittagLevine Children's Hospital, Atrium Health, Charlotte, NC, USA.
Edwin C FerrenLevine Children's Hospital, Atrium Health, Charlotte, NC, USA.
Erika LevineDivision of Medical Genetics and Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mafalda BarbosaDivision of Medical Genetics and Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Joseph BiddleDivision of Genetics, Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
Laurie SadlerDivision of Genetics, Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
Melissa SamonsAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.
Heather ZimmermannAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.
Marcy E RichardsonAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, California, 92656, USA.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundVariants of uncertain significance (VUS) are a substantial barrier to clinical care in genetics, and VUS that are suspected to affect splicing can be particularly difficult to resolve. We used exome sequencing (ES) followed by variant-specific RNA testing to resolve VUS in four separate cases resulting in reclassification to Likely Pathogenic and a positive molecular diagnosis in all cases.

resultsThe variants in these cases include a homozygous variant in ATP6V0A2 in a trio exome case, heterozygous variants in SLC20A2 and in CSF1R in adult proband-only cases, and a heterozygous variant in COL1A1 in a family. All variants were associated with aberrant splicing resulting in loss of function or a major alteration to the protein sequence.

conclusionsThese findings demonstrate the power of targeted RNA testing for reclassifying VUS that have limited direct evidence across a broad range of indications for exome testing.

Indexed as

ExomeExome SequencingGenetic TestingGenetic VariationRNAAdultFemaleHumansMaleMutationRNA SplicingRNARare diseaseRNA analysisVariants of uncertain significance

Identifiers

PMID42380775
PMCPMC13587404

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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 Socratic graph.