Submission Details

VCP was first reported in relation to autosomal dominant inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) in 2004 (Watts et al., PMID: 15034582). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) and inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity - IBMPFD (OMIM:167320) and amyotrophic lateral sclerosis (ALS). 19 missense variants that have been reported in 31 probands in 12 publications (PMIDs: 21145000, 22078486, 23152587, 15034582, 16247064, 17763460, 23000505, 29127544, 19208399, 20335036, 22572540, 25457024) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by animal models, functional alterations in non-patient cells and patient cortical samples (PMIDs: 34289347, 32731393, 31767634, 20147319). Mice expressing both common and highly pathogenic VCP mutations demonstrate both pathological and clinical features of IBMPFD, which include progressive muscle weakness, behavioural deficits and TDP-43 pathology. Furthermore, mutant VCP has consistently been shown to induce cytoplasmic accumulation and increase aggregation propensity of both wild-type and phosphorylated TDP-43 in cultured cells, patient cells and model systems as well as colocalising with other wild-type and mutant ALS-linked proteins. In summary, VCP is definitively associated with autosomal dominant IBMPFD/ALS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen ALS GCEP on December 14, 2021 (SOP Version 8).