Removing uncertainty from variants of unknown significance

McNally discusses Li and colleagues' study assessing the impact of missense variants by performing deep mutational scanning of the SGCB gene and evaluating the cell-surface localization of the sarcoglycan complex for all 6,340 possible amino acid changes. The functional assay scored missense va...

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Bibliographic Details
Published in:The Journal of clinical investigation 2023-06, Vol.133 (12), p.1-1
Main Author: McNally, Elizabeth M
Format: Article
Language:English
Subjects:
Amino acid sequence
Biomedical research
Cell surface
Clinical trials
Diagnosis
Editor Note
Gene therapy
Health care industry
Localization
Muscular dystrophy
Mutation
Proteins
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Summary:McNally discusses Li and colleagues' study assessing the impact of missense variants by performing deep mutational scanning of the SGCB gene and evaluating the cell-surface localization of the sarcoglycan complex for all 6,340 possible amino acid changes. The functional assay scored missense variants based on cell surface production of the sarcoglycan complex. For known pathological variants, the degree of cell surface production correlated with the clinical outcome of loss of ambulation. Variants with less severe functional scores often correlated with slower disease progression, demonstrating a link between variant function and disease severity. The authors used AlphaFold2 to identify domains in this single-pass type 2 transmembrane protein enriched for pathological variants. These findings can aid in the clinical interpretation of SGCB variants and enhance limb-girdle muscular dystrophy diagnosis, and, with clinical trials ongoing for β-sarcoglycan gene replacement therapy, accurate diagnosis is an essential step.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI171497