ClinVar

Description

This variant has been detected in a patient presenting with sensorimotor axonal neuropathy, upper and lower limb muscle weakness with respiratory failure. Nerve biopsy confirmed moderate to severe axonal neuropathy. Electron Microscopy of sural nerve showed moderate loss of myelinated fibres with no abnormal inclusions. Muscle biopsy showed neurogenic atrophy, with ongoing chronic denervation and re-innervation of myofibres with pseudo-dystrophic changes. The c.625C>G variant has not been observed in control population database (gnomAD). The missense change is located within the second IPV motif. Other de novo missense variants in the same amino acid position, e.g. p.Pro209Leu, p.Pro209Gln and p.Pro209Ser have been identified in multiple families with myofibrillar myopathy with neuropathy. There is significant phenotypic variability in Pro209 variants. While the first reported p.Pro209Leu variant leads to a severe myopathy, cardiac and respiratory involvement is only reported in some but not all affected children [PMID: 19085932, 30145633, 32453099]. Later reports of individuals with p.Pro209Ser and p.Pro209Gln variants have adult onset axonal sensorimotor neuropathies with or without myopathy [PMID: 25208129, 28754666, 31853710]. Functional studies of BAG3 showed that the p.Pro209Ala variant did not affect solubility, but there is relative reduction in affinity to heat shock protein Hsp27c [PMID: 30559338]. Based on the current evidence, the BAG3 c.625C>G variant is classified as a variant of uncertain significance (ACMG criteria: PM5, PM2_supporting, PS3_supporting).