Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies

Marco Savarese, Mridul Johari, Katherine Johnson, Meharji Arumilli, Annalaura Torella, Ana Töpf, Anna Rubegni, Marius Kuhn, Teresa Giugliano, Dieter Gläser, Fabiana Fattori, Rachel Thompson, Sini Penttilä, Sara Lehtinen, Sara Gibertini, Alessandra Ruggieri, Marina Mora, Ales Maver, Borut Peterlin, Ami MankodiHanns Lochmüller, Filippo Maria Santorelli, Benedikt Schoser, Lenka Fajkusová, Volker Straub, Vincenzo Nigro, Peter Hackman, Bjarne Udd

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


BACKGROUND: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies. OBJECTIVE: To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants. METHODS: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort. RESULTS: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified. CONCLUSIONS: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.

Original languageEnglish
Pages (from-to)153-166
Number of pages14
JournalJournal of Neuromuscular Diseases
Issue number2
Publication statusPublished - 2020
Externally publishedYes


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