Renan C. Sbruzzi ^1,2 Mayara J. Prado ³ Bibiana S. Fam ^1,3 Helena A. Prolla ^3,4 Alessandra Hellwig ⁵ Grazielle Motta Rodrigues ⁵ Fernanda de-Paris ⁵ Mariana Jobim ⁶ Osvaldo Artigalás ⁷ Yoann Seeleuthner ⁸ Jean-Laurent Casanova ^10,11,8,9 Jacinta Bustamante ^12,8,9 Fernanda S. Vianna ^1,3*

• ¹ Post-Graduate Program in Molecular and Cellular Biology, Department of Genetics and Molecular Biology – Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
• ² Laboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil
• ³ Laboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA),, Porto Alegre, Rio Grande do Sul, Brazil
• ⁴ Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
• ⁵ Laboratory Diagnostic Service, Hospital de Clínicas de Porto Alegre (HCPA), Rio grande do Sul, Porto Alegre, Brazil
• ⁶ Transplant Immunology and Personalized Medicine Unit, Hospital de Clínicas de Porto Alegre (HCPA), Rio Grande do Sul, Porto Alegre, Brazil
• ⁷ Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Rio Grande do Sul, Porto Alegre, Brazil
• ⁸ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
• ⁹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York City, New York, United States
• ¹⁰ Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
• ¹¹ Howard Hughes Medical Institute, New York, United States
• ¹² Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris AP-HP, Paris, France

Inborn errors of immunity (IEI) encompass a broad range of disorders with heterogeneous clinical presentations, often leading to challenges in early diagnosis. This study presents a case of a Brazilian patient with a T-B+NK-severe combined immunodeficiency (SCID) diagnosed at the age of 6 months when was admitted to the hospital due to multiple infectious diseases. Despite undergoing hematopoietic stem cell transplantation (HSCT), the patient had recurrent infections, requiring constant hospital care, including IgG infusions and several antibiotic treatments for the following months. One year after HSCT, presenting mixed chimerism, the patient tested positive for SARS-CoV-2 in nasopharyngeal, duodenum, and intestine samples, with persistent positive tests over a six-month period. Whole exome sequencing identified a private homozygous missense variant (c.1202T>C; p.Leu401Pro) in the Janus Kinase 3 (JAK3) gene. This substitution is located in a highly conserved position, and different bioinformatic variant effect predictors classified the variant as damaging. In silico structural analysis suggested that the variant led to increased structural instability, disrupting the hydrophobic interactions within the SH2 domain, thereby influencing the neighboring residues and potentially altering the interaction between JAK3 and gamma chain (γc) intracellular receptors. This study provides evidence for the novel pathogenicity classification of the variant and highlights the importance of the JAK3 and SH2 domain modulating protein function and their contribution to the SCID pathogenesis.