Submission Details

TFRC was first reported in relation to autosomal recessive TFRC-related combined immunodeficiency in 2016 (Jabara et al., 26642240). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Two missense variants have been reported in eight probands, in three publications (PMID 26642240, 32851577, 38270687). This variant segregated with disease in eight additional family members. Symptoms include recurrent sinopulmonary infections, chronic diarrhea, recurrent epistaxis secondary to thrombocytopenia, mild anemia, and immunodeficiency. Heterozygous carriers were reported to be unaffected. This gene-disease relationship is supported by murine models, functional alteration and rescue experiments in patient cells, in vitro assays showing the gene product performs a biochemical function consistent with the phenotype, and functional alteration in non-patient cells (PMID: 3568132, 6265934, 10192390, 26642240). Patient cells homozygous for the Y20H variant showed defective transferrin uptake and transduction of wild type TfR1 corrected defective transferrin uptake (PMID 26642240). TFRC null mice are embryonic lethal while Tfrc Y20H/Y20H mice had significantly decreased serum IgG, hemoglobin, and MCV compared to controls, as well as impaired receptor internalization on T and B cells (PMID: 26642240, 10192390). In summary, there is definitive evidence to support the relationship between TFRC and autosomal recessive TFRC-related combined immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the SCID-CID GCEP on October 13, 2022. It was re-evaluated on March 20, 2025. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of a new case (PMIDs: 38270687).