Submission Details

Non-loss of function variation of FLNC results in the development of myofibrillar myopathy 5 presenting with a combination and isolated skeletal and cardiac features. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism and phenotypic variability. Loss of function variation causes weakening of myocyte adhesion and is implicated in arrhythmogenic cardiomyopathy and dilated cardiomyopathy without musculoskeletal abnormalities (Verdonschot 2020, PMID 32112656). Conversely, the mechanism of non-loss of function variation for FLNC-induced myopathy is attributed to the aggregation of FLNC and FLNC-binding proteins in muscle and the sarcomere (Furst 2013, PMID 23109048). Therefore, we have split the molecular mechanism, curating only non-loss of function variation for the disease entity [Myopathy, myofibrillar, 5] (OMIM: 609524). Over 22 probands in 9 publications have been published (Vorgerd 2005, PMID 15929027; Kley 2007, PMID 18055494; Kley 2012, PMID 22961544; Shatunov 2009, PMID 19050726; Laun 2010, PMID 20417099; Avila-Smirnow 2012, PMID 27633507; Roldán-Sevilla 2019, PMID 30919686; Gaudreault 2023, PMID 36864778;; Bermúdez-Jiménez 2023, PMID 35952944). There were 16 unique heterozygous variants (12 missense, 1 in-frame deletion, 1 in-frame indel, 1 duplication, and 1 termination in the last exon). One variant (p.Trp2710Ter) was seen in 36 affected individuals across six families and represents a founder effect. Of note, FLNC has a pseudogene located 53.6kb downstream from the functional FLNC gene, and exons 46, 47, and 48 are 98% homologous in the functional and pseudogene (Odgerel 2010, PMID: 20578970).

The gene-disease relationship is also supported by expression studies, protein interaction studies, and model systems (Xie 1998, PMID 979101; Furst 2013, PMID 23109048; van der Ven 2000, PMID 11038172; Gonzalez-Morales 2017 2017, PMID 28732005; Labeit 2006, PMID 16949617; Chevessier 2015, PMID 29859533; Kiselev 2018, PMID 29859533; Ruparelia 2016, PMID 26969713; Agarwal 2012, PMID 34405687), reaching the maximum points for experimental evidence.

In summary, there is definitive evidence supporting the relationship between FLNC non-loss of function variation and autosomal dominant myofibrillar myopathy 5. This has been repeatedly demonstrated in research and clinical settings and upheld over time. This gene-disease pair was originally evaluated as definitive by the ClinGen Hypertrophic Cardiomyopathy GCEP on December 12th, 2017. As a result of this reevaluation, the classification has remained the same; however, the molecular mechanism has been split to include only non-loss of function variation approved on October 26, 2023, by the Hereditary Cardiovascular Disease GCEP.