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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Variant data and genomic coordinates are supplied in Supplementary Data 1 and are also available upon request to the corresponding authors.
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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.
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.
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). https://doi.org/10.1038/s41436-021-01107-y