P.178 Clinical classification of variants in the valosin containing protein gene associated with multisystem proteinopathy

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Mutations in the <i>VCP</i> gene cause a rare heterogeneous disorder that includes myopathy, Paget's disease of the bone, fronto-temporal dementia, motor neuron disease, and parkinsonism, termed VCP related multisystem proteinopathy (VCP-MSP). The heterogeneity in MSP turns the interpretation of <i>VCP</i> novel variants into a challenging process in clinical practice. This study reports novel <i>VCP</i> variants and evaluates evidence to assess their pathogenicity. Novel and/or non-previously clinically characterized variants in the <i>VCP</i> gene were identified in the VCP International Multicentre Study, a retrospective descriptive study which collected clinical, genetic and ancillary test data from 255 patients with VCP. To evaluate their phenotypic level of pathogenicity, we devised a 7-item scoring system that a assessed the presence of: <i>1)</i> autosomal dominant inheritance, <i>2)</i> a clinical phenotype suggestive of VCP-MSP in the patient, <i>3)</i> and in in a first degree relative, <i>4)</i> a novel variant previously identified in another VCP-MSP non-related family, <i>5)</i> rimmed vacuoles or proteins aggregates in the muscle biopsy, <i>6)</i> an amino acid change in a protein location previously reported in VCP-MSP patients and <i>7)</i> a VCP-MSP suggestive muscle MRI. Each item is allocated a value and a total sum scored > 3 points labelled the variant as High Likelihood of Pathogenicity. Then, the novel variant's deleteriousness was predicted by <i>in silico</i> tools and their intrinsic ATPase activity were compared to the VCP-WT and VCP-p.R155H <i>in vitro</i>. Eighteen <i>VCP</i> novel variants were identified in 24 unrelated families. The scoring system defined the variants p.I216M, p.I241S, p.I369F, p.R144H, p.M158T, p.N90D, p.I369T and p.V123M as high-likelihood pathogenic; p.E66K, p.R155G, p.K164Q, p. L96V, p.C209G and p.I27T probable pathogenic and p.K663R, pR89G, p.I353V, and p.I233V as variants of uncertain pathogenicity. Three independent <i>in silico</i> predictions tools categorized 13 variants as possible or probably deleterious. All the mutants induced an increase in ATPase activity compared to VCP-wild type; p.I353V shows similar activity; and p.K663R shows higher activity but no significant difference. After combining the three approaches, 8/18 variants had consistency evidence of pathogenicity. This study describes novel variants associated with VCP-MSP and provides guidance for clinicians in the evaluation of VCP variants.