FOLR1

folate receptor alpha

Basic information

Region (hg38): 11:72189558-72196323

Previous symbols: [ "FOLR" ]

Links

ENSG00000110195

∙ NCBI:2348 ∙ OMIM:136430 ∙ HGNC:3791 ∙ Uniprot:P15328 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

neurodegenerative syndrome due to cerebral folate transport deficiency (Definitive), mode of inheritance: AR
neurodegenerative syndrome due to cerebral folate transport deficiency (Strong), mode of inheritance: AR
neurodegenerative syndrome due to cerebral folate transport deficiency (Definitive), mode of inheritance: AR
neurodegenerative syndrome due to cerebral folate transport deficiency (Supportive), mode of inheritance: AR
neurodegenerative syndrome due to cerebral folate transport deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodegeneration due to cerebral folate deficiency	AR	Biochemical	Diagnosis is critical, as the natural history includes severe neurodegeneration and neurologic impairment, and treatment with folinic acid (it is important to note that response to such treatment is better when initiated in early childhood) can reverse symptoms and improve brain abnormalities and function	Biochemical; Neurologic	19732866; 20857335; 21752681; 22586289; 22734130

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FOLR1 gene.

Cerebral_folate_transport_deficiency (216 variants)
not_provided (53 variants)
Inborn_genetic_diseases (53 variants)
not_specified (27 variants)
FOLR1-related_disorder (9 variants)
Seizure (2 variants)
Epileptic_encephalopathy (1 variants)
Intellectual_disability (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FOLR1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000016729.3. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar			63 clinvar	1 clinvar	65
missense	1 clinvar	6 clinvar	113 clinvar	9 clinvar		129
nonsense	7 clinvar	3 clinvar	2 clinvar			12
start loss		1				1
frameshift	7 clinvar	3 clinvar	2 clinvar			12
splice donor/acceptor (+/-2bp)		3 clinvar		1 clinvar		4
Total	16	16	117	73	1

Highest pathogenic variant AF is 0.0000167285

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FOLR1	protein_coding	protein_coding	ENST00000393679	4	6744

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.126	0.869	124888	8	852	125748	0.00343

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.675	117	139	0.839	0.00000792	1705
Missense in Polyphen		28	38.749	0.7226		505
Synonymous	0.712	47	53.6	0.876	0.00000302	466
Loss of Function	2.48	4	14.0	0.285	7.71e-7	135

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00218	0.00218
Ashkenazi Jewish	0.00635	0.00637
East Asian	0.000163	0.000163
Finnish	0.000554	0.000554
European (Non-Finnish)	0.00240	0.00239
Middle Eastern	0.000163	0.000163
South Asian	0.0141	0.0140
Other	0.00342	0.00343

dbNSFP

Source: dbNSFP

Function: FUNCTION: Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release. Required for normal embryonic development and normal cell proliferation. {ECO:0000269|PubMed:23851396, ECO:0000269|PubMed:23934049, ECO:0000269|PubMed:2527252, ECO:0000269|PubMed:8033114, ECO:0000269|PubMed:8567728}.;
Disease: DISEASE: Neurodegeneration due to cerebral folate transport deficiency (NCFTD) [MIM:613068]: A neurodegenerative disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy and leukodystrophy. {ECO:0000269|PubMed:19732866}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Methotrexate Pathway, Pharmacokinetics;Endocytosis - Homo sapiens (human);Folate Metabolism;Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;Vesicle-mediated transport;Membrane Trafficking;Post-translational protein modification;Metabolism of proteins;Cargo concentration in the ER;Vitamin B9 (folate) metabolism;Transport to the Golgi and subsequent modification;Asparagine N-linked glycosylation;COPI-mediated anterograde transport;COPII-mediated vesicle transport;ER to Golgi Anterograde Transport (Consensus)

Recessive Scores

pRec: 0.264

Intolerance Scores

loftool: 0.829
rvis_EVS: 0.46
rvis_percentile_EVS: 78.28

Haploinsufficiency Scores

pHI: 0.407
hipred: N
hipred_score: 0.322
ghis: 0.398

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: N
gene_indispensability_score: 0.216

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

Gene name: Folr1
Phenotype: embryo phenotype; neoplasm; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; digestive/alimentary phenotype; renal/urinary system phenotype; cellular phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; craniofacial phenotype;

Gene ontology

Biological process: heart looping;neural crest cell migration involved in heart formation;cardiac neural crest cell migration involved in outflow tract morphogenesis;endoplasmic reticulum to Golgi vesicle-mediated transport;receptor-mediated endocytosis;folic acid transport;regulation of transforming growth factor beta receptor signaling pathway;axon regeneration;folic acid metabolic process;COPII vesicle coating;regulation of canonical Wnt signaling pathway;pharyngeal arch artery morphogenesis;anterior neural tube closure;cellular response to folic acid;folate import across plasma membrane
Cellular component: Golgi membrane;nucleus;endosome;endoplasmic reticulum membrane;plasma membrane;cell surface;ER to Golgi transport vesicle membrane;membrane;basolateral plasma membrane;apical plasma membrane;transport vesicle;clathrin-coated vesicle;anchored component of external side of plasma membrane;brush border membrane;endoplasmic reticulum-Golgi intermediate compartment membrane;extracellular exosome
Molecular function: folic acid binding;drug binding;signaling receptor activity;methotrexate binding;folic acid receptor activity