FLVCR2
protein-codingFLVCR heme transporter 2, the group of MicroRNA protein coding host genes|Solute carrier family 49
Gene summary
This gene encodes a member of the major facilitator superfamily. The encoded transmembrane protein is a calcium transporter. Unlike the related protein feline leukemia virus subgroup C receptor 1, the protein encoded by this locus does not bind to feline leukemia virus subgroup C envelope protein. The encoded protein may play a role in development of brain vascular endothelial cells, as mutations at this locus have been associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome. Alternatively spliced transcript variants have been described.[provided by RefSeq, Aug 2010]
- C14orf58
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~84.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009168
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009168
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009168
Submitter: ClinGen
*FLVCR2* was first reported in relation to autosomal recessive Fowler syndrome in 2010 (Meyer et al. 2010 PMID: 20206334). Fowler syndrome, usually a prenatally lethal disorder, is characterized by hydranencephaly, a distinctive glomerular vasculopathy in the central nervous system and retina, and diffuse ischemic lesions of the brain stem, basal ganglia, and spinal cord with calcifications. Additional features include microcephaly, hydrocephalus, ventriculomegaly, joint contractures, and fetal akinesia deformation sequence. Rarely, affected individuals may survive, but are severely impaired (PMID: 25677735). At least 31 unique variants including missense, in-frame indels, nonsense, frameshift, splicing and exonic deletion variants have been reported in humans (PMID: 20518025, 20690116, 38302740, and 30712878). Loss of function is the proposed molecular mechanism for *FLVCR2* dysfunction with variants associated with complete or partial loss of choline transport activity (PMID: 38302740). The *FLVCR2* gene encodes a transmembrane protein that belongs to the major facilitator superfamily of secondary carriers that transport small solutes in response to chemiosmotic ion gradients (PMID: 20206334). Homozygous knockout of the gene in mice recapitulates phenotypes seen in humans with Fowler syndrome (PMID: 32369449, 38302740). In summary, *FLVCR2* is definitively associated with autosomal recessive Fowler syndrome. Evidence supporting this gene-disease relationship includes case-level data, mouse models, and experimental data. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was reviewed and approved by the ClinGen Prenatal GCEP on October 22, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0009168
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009168
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009168
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009168
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009168
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.
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Treatment may involve dietary modification (eg, to restrict trimethylamine precursors), and medical/dietary treatment (eg, with agents such as metronidazole, neomycin, lactulose, copper chlorphyllin, activated charcoal, (E, E)-2, 4-undecadienal) as well as riboflavin supplementation (the use of specific pH soaps may be beneficial as well)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FLVCR2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017791.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 44 | 48 | |||
| missense | 4 | 4 | 102 | 10 | 1 | 121 |
| nonsense | 2 | 3 | 1 | 6 | ||
| start loss | 0 | |||||
| frameshift | 4 | 6 | 10 | |||
| splice donor/acceptor (+/-2bp) | 2 | 3 | 2 | 7 | ||
| Total | 12 | 16 | 109 | 54 | 1 | 192 |
Highest pathogenic variant AF is 0.000039661292
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060261.2 | 10 | MANE Select | |
| Ensembl | ENSP00000238667.4 | 10 | MANE Select | |
| RefSeq | NP_001182212.1 | 10 | Standard | |
| Ensembl | ENSP00000443439.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- transmembrane transport
- heme export
Molecular Function
- heme transporter activity
- heme binding
Cellular Component
- plasma membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000238667
- Coding exons
- 10
- Length
- 84598
- Individuals with no LoFs
- 125702
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 46
- Defined
- 125748
- p
- 0.000183
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0642 | 293 | 296 | 0.990 | 0.0000175 | 3425 |
| Missense (PolyPhen) | 83 | 82.298 | 1.0085 | 1003 | ||
| Synonymous | -0.0521 | 122 | 121 | 1.01 | 0.00000803 | 1097 |
| Loss of Function | 1.82 | 12 | 21.0 | 0.572 | 0.00000102 | 244 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00018 | 0.00014 | rare |
| European (Non-Finnish) | 0.00018 | 0.00018 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as an importer of heme. Also acts as a transporter for a calcium-chelator complex, important for growth and calcium metabolism. {ECO:0000269|PubMed:20823265}.;
Recessive Scores
- pRec
- 0.147
Intolerance Scores
- LoFtool
- 0.633
- RVIS EVS
- 0.35
- RVIS percentile EVS
- 74.49
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.113
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |