Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel

Kelly, M; Caleshu, C; Morales, A; Buchan, J; Wolf, Z; Harrison, S; Cook, S; Dillon, M; Garcia, J; Haverfield, E; Jongbloed, J; Macaya, D; Manrai, A; Orland, K; Richard, G; Spoonamore, K; Thomas, M; Thomson, K; Vincent, L; Walsh, R; Watkins, H; Whiffin, N; Ingles, J; Van Tintelen, J; Semsarian, C; Ware, J; Hershberger, R; Funke, B

Journal article

Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel

Abstract:: Purpose

Integrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach.

Methods

Expert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions.

Results

Adjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing.

Conclusion

These adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Kelly, M., Caleshu, C., Morales, A., Buchan, J., Wolf, Z., Harrison, S., Cook, S., Dillon, M., Garcia, J., Haverfield, E., Jongbloed, J., Macaya, D., Manrai, A., Orland, K., Richard, G., Spoonamore, K., Thomas, M., Thomson, K., Vincent, L., … Funke, B. (2018). Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel. Genetics in Medicine, 20(3), 351–359.

MLA Style

Kelly, M., et al. “Adaptation and Validation of the ACMG/AMP Variant Classification Framework for MYH7-Associated Inherited Cardiomyopathies: Recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel.” Genetics in Medicine, vol. 20, no. 3, Springer Nature, 2018, pp. 351–59.

Chicago Style

Kelly, M, C Caleshu, A Morales, J Buchan, Z Wolf, S Harrison, S Cook, et al. 2018. “Adaptation and Validation of the ACMG/AMP Variant Classification Framework for MYH7-Associated Inherited Cardiomyopathies: Recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel.” Genetics in Medicine 20 (3): 351–59.
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