Clinical and laboratory reporting impact of ACMG-AMP and modified ClinGen variant classification frameworks in MYH7-related cardiomyopathy



ClinGen provides gene-specific guidance for interpretation of sequence variants in MYH7. We assessed laboratory and clinical impact of reclassification by the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) and ClinGen recommendations in 43 MYH7 variants reported by a diagnostic laboratory between 2013 and 2017.


Fifty-two proband reports containing MYH7 variants were reinterpreted by original ACMG-AMP and ClinGen guidelines. Evidence items were compared across schemes and reasons for classification differences recorded. Laboratory impact was assessed by number of recommended report reissues, and reclassifications coded as clinically “actionable” or “equivalent.” Available pedigrees were reviewed to describe projected cascade impact.


ClinGen produced a higher proportion of diagnostic classifications (65% of variants) compared with ACMG-AMP (54%) and fewer variants of uncertain significance (30% versus 42%). ClinGen classification resulted in actionable changes in 18% of variants with equal upgrades and downgrades from original report. ClinGen’s revisions to PM1 and PS4 contributed to classification differences in 21% and 19% of variants respectively. Each classification change per proband report impacted, on average, 3.1 cascade reports with a further 6.3 first- and second-degree relatives potentially available for genotyping per family.


ClinGen’s gene-specific criteria provide expert-informed guidance for interpretation of MYH7 sequence variants. Periodic re-evaluation improves diagnostic confidence and should be considered by clinical and laboratory teams.

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Fig. 1: Variant classification comparisons across original report, ACMG and ClinGen schemes.

Data availability

Variant data and genomic coordinates are supplied in Supplementary Data 1 and are also available upon request to the corresponding authors.


  1. 1.

    Maron, B. J., Gardin, J. M., Flack, J. M., Gidding, S. S., Kurosaki, T. T. & Bild, D. E. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. 92, 785–789 (1995).

    CAS  Article  Google Scholar 

  2. 2.

    Maron, B. J., Maron, M. S. & Semsarian, C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J. Am. Coll. Cardiol. 60, 705–715 (2012).

    Article  Google Scholar 

  3. 3.

    Das, K. J., Ingles, J., Bagnall, R. D. & Semsarian, C. Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment. Genet. Med. 16, 286–293 (2014).

    Article  Google Scholar 

  4. 4.

    Cirino, A. L. & Ho, C. in GeneReviews (eds Adam, M. P. et al.). Hypertrophic cardiomyopathy overview. (University of Washington, Seattle, 1993).

  5. 5.

    Walsh, R. et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet. Med. 19, 192–203 (2017).

    Article  Google Scholar 

  6. 6.

    Ho, C. Y. et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation. 138, 1387–1398 (2018).

    Article  Google Scholar 

  7. 7.

    Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015).

    Article  Google Scholar 

  8. 8.

    Bean, L. J. H. & Hegde, M. R. Clinical implications and considerations for evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines. Genome Med. 9, 111 (2017).

    Article  Google Scholar 

  9. 9.

    Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 536, 285–291 (2016).

    CAS  Article  Google Scholar 

  10. 10.

    Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 581, 434–443 (2020).

    CAS  Article  Google Scholar 

  11. 11.

    Karczewski, K. J. et al. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. Preprint at bioRxiv (2019)

  12. 12.

    Ghosh, R., Harrison, S. M., Rehm, H. L., Plon, S. E. & Biesecker, L. G., ClinGen Sequence Variant Interpretation Working Group. Updated recommendation for the benign stand-alone ACMG/AMP criterion. Hum. Mutat. 39, 1525–1530 (2018).

    Article  Google Scholar 

  13. 13.

    Abou Tayoun, A. N. et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum. Mutat. 39, 1517–1524 (2018).

    Article  Google Scholar 

  14. 14.

    Amendola, L. M. et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am. J. Hum. Genet. 98, 1067–1076 (2016).

    CAS  Article  Google Scholar 

  15. 15.

    Nykamp, K. et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet. Med. 19, 1105–1117 (2017).

    Article  Google Scholar 

  16. 16.

    Rivera-Munoz, E. A. et al. ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation. Hum. Mutat. 39, 1614–1622 (2018).

    Article  Google Scholar 

  17. 17.

    Kelly, M. A. 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. Genet. Med. 20, 351–359 (2018).

    Article  Google Scholar 

  18. 18.

    Landrum, M. J. et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 42(Database issue), D980–5 (2014).

    CAS  Article  Google Scholar 

  19. 19.

    Gelb, B. D. et al. ClinGen’s RASopathy Expert Panel consensus methods for variant interpretation. Genet. Med. 20, 1334–1345 (2018).

    Article  Google Scholar 

  20. 20.

    Lee, K. et al. Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants. Hum. Mutat. 39, 1553–1568 (2018).

    Article  Google Scholar 

  21. 21.

    Mester, J. L. et al. Gene-specific criteria for PTEN variant curation: recommendations from the ClinGen PTEN Expert Panel. Hum. Mutat. 39, 1581–1592 (2018).

    Article  Google Scholar 

  22. 22.

    Morales, A. et al. Variant interpretation for dilated cardiomyopathy: refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study. Circ. Genom. Precis. Med. 13, e002480 (2020).

    CAS  Article  Google Scholar 

  23. 23.

    Mattivi, C. L. et al. Clinical utility of a phenotype enhanced MYH7-specific variant classification framework in hypertrophic cardiomyopathy genetic testing. Circ. Genom. Precis. Med. 13, 453–459 (2020).

  24. 24.

    Lawal, T. A. et al. Disclosure of cardiac variants of uncertain significance results in an exome cohort. Clin. Genet. 93, 1022–1029 (2018).

    CAS  Article  Google Scholar 

  25. 25.

    Macklin, S. K., Jackson, J. L., Atwal, P. S. & Hines, S. L. Physician interpretation of variants of uncertain significance. Fam. Cancer. 18, 121–126 (2019).

    Article  Google Scholar 

  26. 26.

    Bennett, J. S. et al. Reclassification of variants of uncertain significance in children with inherited arrhythmia syndromes is predicted by clinical factors. Pediatr. Cardiol. 40, 1679–1687 (2019).

    Article  Google Scholar 

  27. 27.

    El Mecky, J. et al. Reinterpretation, reclassification, and its downstream effects: challenges for clinical laboratory geneticists. BMC Med. Genomics. 12, 170 (2019).

    Article  Google Scholar 

  28. 28.

    Richards, C. S. et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet. Med. 10, 294–300 (2008).

    CAS  Article  Google Scholar 

  29. 29.

    Harris, P. A. et al. The REDCap consortium: building an international community of software platform partners. J. Biomed. Inform. 95, 103208 (2019).

    Article  Google Scholar 

  30. 30.

    Homburger, J. R. et al. Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation. Proc. Natl. Acad. Sci. U. S. A. 113, 6701–6706 (2016).

    CAS  Article  Google Scholar 

  31. 31.

    ClinGen. ClinGen sequence variant interpretation recommendation for PM2 version 1.0. (2020).

  32. 32.

    Wong, E. K. et al. Perceptions of genetic variant reclassification in patients with inherited cardiac disease. Eur. J. Hum. Genet. 27, 1134–1142 (2019).

  33. 33.

    Bombard, Y. et al. The responsibility to recontact research participants after reinterpretation of genetic and genomic research results. Am. J. Hum. Genet. 104, 578–595 (2019).

    CAS  Article  Google Scholar 

  34. 34.

    David, K. L. et al. Patient re-contact after revision of genomic test results: points to consider-a statement of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 21, 769–771 (2019).

    Article  Google Scholar 

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The authors acknowledge and value the contributions of clinical and laboratory personnel involved in the care and diagnosis of these patients.

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Corresponding authors

Correspondence to Tiong Y. Tan or Ivan Macciocca.

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Ethics Declaration

This project received Human Research Ethics Committee approval (HREC/52933/RCHM-2019) and site-specific approval through Murdoch Children’s Research Institute and Royal Children’s Hospital (Parkville, Victoria, Australia) in 2019.

Competing interests

C.M.R., T.Y.T., S.-J.P., B.C., S.L., and I.M. were salaried employees of the Victorian Clinical Genetics Services, part of the Murdoch Children’s Research Institute, Parkville, Victoria, Australia for the duration of this project. P.A.J. is a salaried employee of the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Parkville, Australia. There are no additional financial engagements or holdings to disclose.

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Richmond, C.M., James, P.A., Pantaleo, SJ. et al. Clinical and laboratory reporting impact of ACMG-AMP and modified ClinGen variant classification frameworks in MYH7-related cardiomyopathy. Genet Med (2021).

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