Submission Details

TF was first reported in relation to autosomal recessive atransferrinemia in 2000 (Beutler E et al., PMID:11110675). Although reports of a transferrin defect causing congenital atransferrinemia date back to 1961. Cases first identified in the 1900s that have since been genotyped are scored in this curation. Atransferrinemia is a rare hematologic disease characterized by microcytic, hypochromic anemia and iron overload, and that can be fatal if left untreated. Some patients present with pallor, fatigue, and growth retardation.

Ten variants (eight missense, one synonymous, one frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Variants in this gene have been reported in 9 probands in 7 publications (PMIDs:11110675, 32028041, 12111369, 15466165, 23888904, 18097132, 19696475).

This gene-disease relationship is supported by biochemical function, an expression study, and a mouse model (PMIDs:10945247, 25970244, 10910930). The biochemical function of TF in iron binding and transport is well established. This role is consistent with the phenotype of the patients scored in this curation. The kinetic studies and X-ray crystallography supporting this function are reviewed by Hirose (PMID:10945247). RNA sequencing of total RNA from 20 human tissues shows specific expression in the liver and fetal liver, relevant tissues to this disease (PMID:25970244). A known hypotransferrinemic mouse line, exhibiting transferrin deficiency, marked anemia, hyperabsorption of iron, and elevated hepatic iron, was investigated and found to have a splice defect in the mouse transferrin gene (PMID:10910930).

In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date September 26, 2025.

*TF *was first reported in relation to autosomal recessive atransferrinemia in 2000 (Beutler E et al., PMID:11110675). Although reports of a transferrin defect causing congenital atransferrinemia date back to 1961. Cases first identified in the 1900s that have since been genotyped are scored in this curation. Atransferrinemia is a rare hematologic disease characterized by microcytic, hypochromic anemia and iron overload, and that can be fatal if left untreated. Some patients present with pallor, fatigue, and growth retardation.

Ten variants (eight missense, one synonymous, one frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Variants in this gene have been reported in 9 probands in 7 publications (PMIDs:11110675, 32028041, 12111369, 15466165, 23888904, 18097132, 19696475).

This gene-disease relationship is supported by biochemical function, an expression study, and a mouse model (PMIDs:10945247, 25970244, 10910930). The biochemical function of TF in iron binding and transport is well established. This role is consistent with the phenotype of the patients scored in this curation. The kinetic studies and X-ray crystallography supporting this function are reviewed by Hirose (PMID:10945247). RNA sequencing of total RNA from 20 human tissues shows specific expression in the liver and fetal liver, relevant tissues to this disease (PMID:25970244). A known hypotransferrinemic mouse line, exhibiting transferrin deficiency, marked anemia, hyperabsorption of iron, and elevated hepatic iron, was investigated and found to have a splice defect in the mouse transferrin gene (PMID:10910930).

In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.