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 (Supportive), 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 (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 (11 variants)
• not provided (3 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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	49	1	51
missense	1	2	105	2		110
nonsense	6	2	2			10
start loss		1				1
frameshift	6		1			7
inframe indel						0
splice donor/acceptor (+/-2bp)		3				3
splice region			5	9		14
non coding			3	25	9	37
Total	13	8	112	76	10

Highest pathogenic variant AF is 0.0000131

Variants in FOLR1

This is a list of pathogenic ClinVar variants found in the FOLR1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-72189646-C-G		Cerebral folate transport deficiency	Uncertain significance (Jan 12, 2018)
11-72189738-G-A		not specified	Likely benign (Jul 10, 2017)
11-72189741-G-A		Cerebral folate transport deficiency	Uncertain significance (Jan 13, 2018)
11-72189768-C-T		not specified	Likely benign (Jul 08, 2016)
11-72189920-G-A		Gastrointestinal stromal tumor	Benign (Jun 29, 2018)
11-72190084-G-A			Benign (Jun 23, 2018)
11-72190447-G-A			Benign (May 24, 2019)
11-72190534-C-T			Benign (Jun 29, 2018)
11-72190626-C-T			Benign (May 24, 2019)
11-72190801-A-C			Benign (May 24, 2019)
11-72192160-C-T		Cerebral folate transport deficiency	Conflicting classifications of pathogenicity (Dec 31, 2018)
11-72192174-A-G			Likely pathogenic (Jan 27, 2017)
11-72192181-A-G		Cerebral folate transport deficiency	Uncertain significance (Jun 24, 2021)
11-72192182-G-A		not specified	Likely benign (Jan 26, 2018)
11-72192183-C-T		Cerebral folate transport deficiency	Uncertain significance (Aug 16, 2022)
11-72192184-G-A		Cerebral folate transport deficiency • Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 10, 2023)
11-72192186-A-G		Cerebral folate transport deficiency • Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 25, 2022)
11-72192190-C-T		Cerebral folate transport deficiency	Uncertain significance (Aug 24, 2021)
11-72192191-A-G		Cerebral folate transport deficiency	Likely benign (Oct 28, 2022)
11-72192195-C-A		Inborn genetic diseases • Cerebral folate transport deficiency	Uncertain significance (Jan 01, 2023)
11-72192205-TC-T			Pathogenic (Apr 28, 2017)
11-72192215-G-A		Cerebral folate transport deficiency	Likely benign (May 08, 2023)
11-72192218-G-T		Cerebral folate transport deficiency • not specified • Inborn genetic diseases	Uncertain significance (Jan 11, 2023)
11-72192226-T-C		Cerebral folate transport deficiency	Uncertain significance (Jan 27, 2022)
11-72192227-A-T		Cerebral folate transport deficiency	Likely benign (Oct 12, 2023)

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