FLVCR1

FLVCR heme transporter 1, the group of Solute carrier family 49

Basic information

Region (hg38): 1:212858274-212899363

Previous symbols: [ "AXPC1" ]

Links

ENSG00000162769 ∙ NCBI:28982 ∙ OMIM:609144 ∙ HGNC:24682 ∙ Uniprot:Q9Y5Y0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• posterior column ataxia-retinitis pigmentosa syndrome (Definitive), mode of inheritance: AR
• posterior column ataxia-retinitis pigmentosa syndrome (Strong), mode of inheritance: AR
• posterior column ataxia-retinitis pigmentosa syndrome (Definitive), mode of inheritance: AR
• posterior column ataxia-retinitis pigmentosa syndrome (Supportive), mode of inheritance: AR
• FLVCR1-related retinopathy with or without ataxia (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ataxia, posterior column, with retinitis pigmentosa	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic; Ophthalmologic	9409377; 9855554; 21070897; 21267618; 22279524; 22483575

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FLVCR1 gene.

• not provided (351 variants)
• Posterior column ataxia-retinitis pigmentosa syndrome (160 variants)
• Inborn genetic diseases (31 variants)
• not specified (15 variants)
• Retinal dystrophy (9 variants)
• Retinitis pigmentosa (6 variants)
• Hereditary sensory and autonomic neuropathy;Retinitis pigmentosa (1 variants)
• FLVCR1-related condition (1 variants)
• Abnormal retinal morphology;Sensory neuropathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FLVCR1 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			11	81	2	94
missense	5	3	180	2	2	192
nonsense	3	3	1			7
start loss	1	1				2
frameshift	10	5	3			18
inframe indel	1		4			5
splice donor/acceptor (+/-2bp)	1	1				2
splice region		1	7	6		14
non coding			67	34	44	145
Total	21	13	266	117	48

Highest pathogenic variant AF is 0.0000527

Variants in FLVCR1

This is a list of pathogenic ClinVar variants found in the FLVCR1 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-212858285-C-G		Posterior column ataxia-retinitis pigmentosa syndrome	Uncertain significance (Jan 13, 2018)
1-212858287-G-C		Posterior column ataxia-retinitis pigmentosa syndrome	Uncertain significance (Jan 13, 2018)
1-212858296-GT-G		Posterior column ataxia-retinitis pigmentosa syndrome	Uncertain significance (Jun 14, 2016)
1-212858299-G-T		Posterior column ataxia-retinitis pigmentosa syndrome	Uncertain significance (Jan 13, 2018)
1-212858349-G-A		Posterior column ataxia-retinitis pigmentosa syndrome	Uncertain significance (Jan 13, 2018)
1-212858366-G-A		Posterior column ataxia-retinitis pigmentosa syndrome	Likely benign (Jan 13, 2018)
1-212858367-C-T		Posterior column ataxia-retinitis pigmentosa syndrome	Benign (Jan 13, 2018)
1-212858417-G-A		Posterior column ataxia-retinitis pigmentosa syndrome	Uncertain significance (Jan 12, 2018)
1-212858446-C-T			Uncertain significance (Feb 17, 2023)
1-212858454-T-C		Inborn genetic diseases • Posterior column ataxia-retinitis pigmentosa syndrome	Pathogenic/Likely pathogenic (May 04, 2022)
1-212858455-G-T		Inborn genetic diseases	Pathogenic (Nov 01, 2022)
1-212858458-G-A			Likely benign (Dec 30, 2023)
1-212858459-C-T		Inborn genetic diseases • Retinal dystrophy	Uncertain significance (Nov 01, 2022)
1-212858461-G-C			Likely benign (Dec 06, 2021)
1-212858467-C-T			Likely benign (Dec 01, 2023)
1-212858470-T-A			Uncertain significance (Oct 30, 2019)
1-212858470-T-C			Likely benign (Jul 22, 2022)
1-212858475-AG-A			Pathogenic (Oct 25, 2022)
1-212858477-G-A		Retinal dystrophy • Inborn genetic diseases	Uncertain significance (Nov 15, 2022)
1-212858478-G-A			Uncertain significance (Dec 24, 2019)
1-212858482-G-A			Uncertain significance (Sep 01, 2016)
1-212858492-C-T			Likely benign (Jan 11, 2024)
1-212858494-C-T		Posterior column ataxia-retinitis pigmentosa syndrome	Conflicting classifications of pathogenicity (Apr 24, 2022)
1-212858501-C-G			Uncertain significance (Jun 30, 2023)
1-212858501-C-T			Uncertain significance (Nov 11, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FLVCR1	protein_coding	protein_coding	ENST00000366971	10	41109

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00131	0.997	125704	0	44	125748	0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.852	243	283	0.858	0.0000130	3516
Missense in Polyphen		50	69.436	0.72009		880
Synonymous	-0.193	119	116	1.02	0.00000567	1181
Loss of Function	2.77	9	23.5	0.383	0.00000108	292

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000449	0.000449
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000202	0.000202
Middle Eastern	0.000109	0.000109
South Asian	0.000196	0.000196
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Isoform 1: Heme transporter that exports cytoplasmic heme. It can also export coproporphyrin and protoporphyrin IX, which are both intermediate products in the heme biosynthetic pathway. Does not export bilirubin. Heme export depends on the presence of HPX and is required to maintain intracellular free heme balance, protecting cells from heme toxicity. Heme export provides protection from heme or ferrous iron toxicities in liver, brain, sensory neurons and during erythtopoiesis, a process in which heme synthesis intensifies. Causes susceptibility to FeLV-C in vitro. {ECO:0000269|PubMed:10400745, ECO:0000269|PubMed:15369674, ECO:0000269|PubMed:20610401, ECO:0000269|PubMed:27923065}.
• Disease: DISEASE: Posterior column ataxia with retinitis pigmentosa (PCARP) [MIM:609033]: A neurodegenerative syndrome beginning in infancy with areflexia and retinitis pigmentosa. Nyctalopia (night blindness) and peripheral visual field loss are usually evident during late childhood or teenage years, with subsequent progressive constriction of the visual fields and loss of central retinal function over time. A sensory ataxia caused by degeneration of the posterior columns of the spinal cord results in a loss of proprioceptive sensation that is clinically evident in the second decade of life and gradually progresses. Scoliosis, camptodactyly, achalasia, gastrointestinal dysmotility, and a sensory peripheral neuropathy are variable features of the disease. Affected individuals have no clinical or radiological evidence of cerebral or cerebellar involvement. {ECO:0000269|PubMed:21070897, ECO:0000269|PubMed:21267618}. Note=The disease is caused by mutations affecting the gene represented in this entry. Defective neuronal heme transmembrane export due to FLVCR1 mutations may abrogate the neuroprotective effects of neuroglobin and initiate an apoptotic cascade that results in the selective degeneration of photoreceptors in the neurosensory retina and sensory neurons in the posterior spinal cord.; DISEASE: Note=Defects in FLVCR1 are a cause of a sensory neuropathy resulting in pain insensitivity. Patients have decreased sensing of pain, temperature and touch. Self-injury, ulcers and amputations are commonly observed in affected individuals. {ECO:0000269|PubMed:27923065}.
• Pathway: Transport of small molecules;Iron uptake and transport (Consensus)

Recessive Scores

• pRec: 0.112

Intolerance Scores

• loftool: 0.465
• rvis_EVS: 0.02
• rvis_percentile_EVS: 55.45

Haploinsufficiency Scores

• pHI: 0.0976
• hipred: N
• hipred_score: 0.494
• ghis: 0.552

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.650

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Flvcr1
• Phenotype: skeleton phenotype; immune system phenotype; limbs/digits/tail phenotype; 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); hematopoietic system phenotype; 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); normal phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: flvcr1
• Affected structure: nucleate erythrocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: blood vessel development;in utero embryonic development;mitochondrial transport;cellular iron ion homeostasis;multicellular organism development;heme transport;erythrocyte differentiation;multicellular organism growth;embryonic digit morphogenesis;erythrocyte maturation;regulation of organ growth;spleen development;embryonic skeletal system morphogenesis;transmembrane transport;head morphogenesis;heme export
• Cellular component: mitochondrion;plasma membrane;integral component of plasma membrane;mitochondrial membrane
• Molecular function: transporter activity;protein binding;heme transporter activity;heme binding