SLC19A1 (previously known as RFC1) encodes the reduced folate carrier (RFC) protein, the primary transporter for folates into cells. SLC19A1 was first reported in relation to autosomal recessive immunodeficiency 114, folate-responsive in 2020 (Svaton et al., PMID: 32276275). The disease is characterized by poor growth, oral ulcers, mucosal bleeding, recurrent respiratory tract infections, impaired T-cell proliferation, and decreased red blood cell folate levels.
Three variants (two missense, and one deletion) that have been reported in four probands in three publications (PMIDs: 36517554, 36745868, 32276275) are included in this curation. The first patient (PMID: 32276275) with a homozygous missense variant showed signs of anemia and hyperhomocysteinemia, while denying having any bleeding, limb numbness, any other neurologic symptoms, or symptoms of glossitis. Two other patients with different homozygous missense mutations also reported oral bleeding, respiratory distress, and abnormal T-cell count (PMID: 36517554). Another patient with a homozygous deletion variant reported diarrhea, recurrent fevers, and gradually developed curly gray hair (PMID: 36745868).
This gene-disease relationship is also supported by animal models and rescues (PMID: 11266438). No homozygous RFC1-null pups were identified, indicating that the mutation was embryonic lethal, until a dose of 1 mg of folic acid per day was administrated to RFC1 +/−dams. While there is no established null human probands, there is also no evidence to contradict that null variants in SLC19A1 for humans would also cause a lethality.
In summary, there is limited 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 PIRD GCEP on the meeting date 16th September 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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