GeneBe

FOLR1

protein-coding

folate receptor alpha

Gene summary

The protein encoded by this gene is a member of the folate receptor family. Members of this gene family bind folic acid and its reduced derivatives, and transport 5-methyltetrahydrofolate into cells. This gene product is a secreted protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form. Mutations in this gene have been associated with neurodegeneration due to cerebral folate transport deficiency. Due to the presence of two promoters, multiple transcription start sites, and alternative splicing, multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2009]

Previous symbols:
  • FOLR

MANE transcript

NM_016729.3

Inheritance

AR

ClinVar variants

P:34U:121B:80

Top phenotype

Neurodegeneration due to cerebral folate deficiency

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr11:72,189,558-72,196,323

External References & Databases

Ensembl (ENSG00000110195)NCBI Gene (2348)OMIM (136430)HGNC:3791GenCCUniProt (P15328)AlphaFoldClinVar (FOLR1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~6.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodegenerative syndrome due to cerebral folate transport deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013110

Submitter: ClinGen

*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.

neurodegenerative syndrome due to cerebral folate transport deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013110

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

neurodegenerative syndrome due to cerebral folate transport deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013110

Submitter: Labcorp Genetics (formerly Invitae)

neurodegenerative syndrome due to cerebral folate transport deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013110

Submitter: PanelApp Australia

neurodegenerative syndrome due to cerebral folate transport deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013110

Submitter: Orphanet

neurodegenerative syndrome due to cerebral folate transport deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013110

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodegeneration due to cerebral folate deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: 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

Refs: 19732866; 20857335; 21752681; 22586289; 22734130Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOLR1 variants in ClinVar

8 Conditions Cataloged
Cerebral folate transport deficiencyTotal: 224
not providedTotal: 63
Inborn genetic diseasesTotal: 54
not specifiedTotal: 35
FOLR1-related disorderTotal: 13
SeizureTotal: 2
Epileptic encephalopathyTotal: 1
Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016729.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
68
clinvar
1
clinvar
 70
missense
1
clinvar
7
clinvar
116
clinvar
10
clinvar
 134
nonsense
9
clinvar
3
clinvar
1
clinvar
 13
start loss
1
clinvar
 1
frameshift
7
clinvar
3
clinvar
2
clinvar
 12
splice donor/acceptor (+/-2bp)
3
clinvar
1
clinvar
1
clinvar
 5
Total1717121791235

Highest pathogenic variant AF is 0.000103463484

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_016729.3RefSeqNP_057941.14MANE Select
ENST00000393676.5EnsemblENSP00000377281.34MANE Select
NM_000802.3RefSeqNP_000793.14Standard
NM_016724.3RefSeqNP_057936.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Methotrexate Pathway, Pharmacokinetics
  • Endocytosis - Homo sapiens (human)
  • Folate Metabolism
  • Ebola Virus Pathway on Host
  • Ebola Virus Pathway on Host

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

Molecular Function

  • folic acid binding
  • drug binding
  • signaling receptor activity
  • methotrexate binding
  • folic acid receptor activity

Cellular Component

  • Golgi membrane
  • nucleus
  • endosome
  • endoplasmic reticulum membrane
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000393679
Coding exons
4
Length
6744
Individuals with no LoFs
124888
Homozygous LoFs
8
Heterozygous LoFs
852
Defined
125748
p
0.00343
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6751171390.8390.000007921705
Missense (PolyPhen)2838.7490.7226505
Synonymous0.7124753.60.8760.00000302466
Loss of Function2.48414.00.2857.71e-7135

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000620.00062rare
Latino/Admixed American0.00160.0015notable
Ashkenazi Jewish0.00640.0064notable
East Asian0.000160.00016rare
Finnish0.000550.00055rare
European (Non-Finnish)0.00240.0024notable
South Asian0.0140.014notable
Other0.00340.0034notable

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.264

Intolerance Scores

LoFtool
0.829
RVIS EVS
0.46
RVIS percentile EVS
78.28

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.216

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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