ClinVar

In a 16-year-old boy (P3) of European descent with immunodeficiency-121 with autoinflammation (IMD121; 620807), van der Made et al. (2024) identified a de novo heterozygous c.601G-C transversion (c.601G-C, NM_002801) in exon 7, resulting in a gly201-to-arg (G201R) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including dbSNP, ExAC, and gnomAD. The mutation resulted in the same amino acid substitution as a different point mutation (c.601G-A; 176847.0006) identified in other patients with the disorder. Immunoblot analysis of fibroblasts derived from the patient showed an abnormal PSMB10 band, suggesting that the mutant protein had altered physiochemical characteristics that could be consistent with a dominant-negative effect. Functional studies of the variant were not performed. The patient (P3) died at 16 years of age.