FLVCR1

Inheritance Pattern: AR

Disease ID:MONDO:0100449

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012177

Submitter: Illumina

The FLVCR1 gene is located on chromosome 1 at 1q32.3 and encodes the FLVCR heme transporter 1 protein, a member of the major facilitator superfamily of transporter proteins which is specifically involved in the transmembrane transport of cytoplasmic heme. The protein plays a critical role in erythropoiesis by protecting the developing erythroid cells from heme toxicity. FLVCR1 was first reported in relation to autosomal recesssive posterior column ataxia-retinitis pigmentosa syndrome in 2010 (21070897: Rajadhyaksha et al. 2010). At least 11 unique variants (including missense and loss of function variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental evidence. Variants in this gene have been reported in at least seven probands in three publications (27923065: Chiabrando et al. 2016; 27353947: Tiwari et al. 2016; 30656474: Kuehlewein et al. 2019). Variants in this gene segregated with disease in two families. Clinical variability was noted with affected individuals presenting with either posterior column ataxia with retinitis pigmentosa (PCARP), non-syndromic retinitis pigmentosa, or hereditary sensory and autonomic neuropathy (HSAN). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. It is suggested that the underlying disease mechanism may be heme overload (27923065: Chiabrando et al. 2016). This gene-disease relationship is supported by expression studies and in vitro functional assays in patient and non-patient cells (21070897: Rajadhyaksha et al. 2010; 27923065: Chiabrando et al. 2016). In summary, FLVCR1 is definitively associated with autosomal recessive posterior column ataxia-retinitis pigmentosa syndrome.

Inheritance Pattern: AR

Disease ID:MONDO:0012177

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0100449

Submitter: ClinGen

FLVCR1 was first reported in relation to autosomal recessive FLVCR1-related retinopathy with or without ataxia (also known as posterior column ataxia-retinitis pigmentosa syndrome; PCARP) in 2010 (Rajadhyaksha et al., PMID: 21070897). This condition is characterized by childhood onset retinal dystrophy and progressive sensory ataxia. At least 321 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc) have been reported in humans (ClinVar database). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. This curation includes 12 variants (missense, frameshift, nonsense, intronic) from 11 probands from 5 publications (Rajadhyaksha et al, 2010, PMID: 21070897; Ishiura et al, 2011, PMID: 21267618; Castori et al, 2017, PMID: 28766925; Kuehlewein et al, 2019, PMID 30656474; Grudzinska Pechhacker et al, 2020, PMID: 32822874) in addition to segregation data (Rajadhyaksha et al, 2010, PMID: 21070897). More data is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Experimental evidence included qPCR expression data in mice (Rajadhyaksha et al, 2010, PMID: 21070897), functional studies in patient cells, and a homology model of the protein (Grudzinska Pechhacker et al, 2020, PMID: 32822874). In summary, FLVCR1 has a definitive relationship with FLVCR1-related retinopathy with or without ataxia. This classification was approved by the ClinGen Retina GCEP on August 5, 2021.

Inheritance Pattern: AR

Disease ID:MONDO:0012177

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012177

Submitter: Orphanet