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Updated: May 31, 2026
Pre-Implantation Genetic Testing for Aneuploidy on a Semiconductor Based Next-Generation Sequencing Platform
Published on: August 17, 2022
Correcting PVS1 overestimation: clinical insights into rescue transcripts and variant reclassification in 4 prenatal
Xiangyou Leng1, Jin Wang1, Danying Yi1
1Department of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Women's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China.
Background:
As NGS has become more widely used in the diagnosis of rare diseases, an increasing number of variants of uncertain significance (VUS) have been detected, and their interpretation remains challenging. In particular,when a LOF variant in a non-conserved exon of the MANE transcript is detected by ES, yet the individual carrying this variant exhibits no clinical manifestations. In this context, the ACMG Splicing Subgroup introduced the term 'rescue transcripts' to guide the interpretation of LOF variants located within non-conserved exons.
Methods:
In this study, the properties of four different variants were characterised using in silico predictions, protein structural analysis, population frequency data, and clinical observations.
Results:
Three variants (AMMECR1:c.220C>T; GLI2:c.162_163delCT; COL11A1:c.1245+1G>A) were reclassified as likely benign (LB)/VUS because rescue transcripts were identified in the corresponding genes. Another variant (EHMT1:exon2-10 del) was reclassified as a VUS, as exons 2-10 may represent non-constitutive exons, and the deletion (p.8A-549E del) may not affect protein function. Therefore, this variant should not be assigned a PVS1 code.
Conclusion:
The presented case studies provide actionable recommendations for identifying rescue transcripts and enhance the understanding of the correct application of PVS1 codes.
