Fig. 1.

Identification of a rare genetic variant in AMFR in a patient with severe VZV infection and HLH. A Characteristics of the monoallelic AMFR variant. B Pedigree showing heterozygous inheritance of the AMFR R594C variant inherited from the mother. C Sanger sequencing confirming the presence of the AMFR R594C variant in the patient (P1), the patient’s mother, and siblings. D Protein structure of AMFR with localization of the R594C variant in the G2BR domain. E Protein alignment showing conservation of Arginine at position 594 in AMFR across different species. F AMFR mRNA levels were measured using RT-qPCR of whole-cell lysates of PBMCs from healthy controls, P1, and his mother. Statistics was done by ordinary 1-way ANOVA. not significant (ns). CADD, combined annotation dependent depletion; MSC, mutation significance cutoff; SIFT, sorting intolerant from tolerant; gnomAD, the genome aggregation database; GDI, Gene Damage Index; RING, really interesting new gene; CUE, coupling of ubiquitin conjugation to ER degradation; G2BR, Ube2g2-binding region; VIM, p97/VCP-interacting motif