FOLR1 was first reported in relation to autosomal recessive neurodegenerative syndrome due to cerebral folate transport deficiency in 2009 (Steinfeld et al., PMID: 19732866). FOLR1 encodes a protein involved in folic acid binding. The disorder is characterized by progressive neurologic deterioration with developmental delay, intellectual disability, seizures, and movement disorders.
Fourteen variants (missense, nonsense, splice, inframe duplication) that have been reported in 17 probands in 10 publications (PMIDs: 19732866, 20857335, 21752681, 22586289, 24091540, 24556562, 25274592, 27066576, 27328863, 27743887) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. Pathogenic variants result in loss of folate binding in patient cells (PMID: 19732866).
In summary, there is definitive evidence supporting the relationship between FOLR1 and autosomal recessive neurodegenerative syndrome due to cerebral folate transport deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017 (SOP Version 5). As of July 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
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