Submission Details

The relationship between CHM and choroideremia was evaluated using the ClinGen Clinical Validity Framework as of August 26, 2020. Choroideremia (CHM) is an X-linked disorder characterized by progressive degeneration of the photoreceptors, retinal pigment epithelium (RPE) and underlying choroid. Affected males present with progressive retinal degeneration leading to night blindness in childhood or teens, develop loss of peripheral vision, and have complete loss of vision by middle age. Heterozygous females are usually asymptomatic, but characteristic areas of chorioretinal degeneration can be observed, most likely representing clonal areas of disease due to random X inactivation (Mosajee et al, 2014, PMID 23963298; MacDonald et al, 2015, PMID 20301511; Dimopoulos et al, 2017, PMID 28520608). The CHM gene product, known as the Rab Escort Protein 1 (REP1), is involved in the lipid modification (prenylation) of Rab GTPases, a process which is essential for the role of Rab GTPases in intracellular vesicular transport (Mitsios et al, 2018, PMID 30627697). Rearrangements in this gene, including deletions and translocations, were first reported in 1990 (Cremers et al, PMID: 2215697), and single nucleotide variants were first published in 1992 (van den Hurk et al, PMID 1598901). Since then, over 300 variants in CHM have been identified as pathogenic or likely pathogenic for choroideremia (https://databases.lovd.nl/shared/variants/CHM/unique). The majority of variants are loss of function, such as nonsense, frameshift, and canonical splice site variants. However, a few missense variants have been reported (Dimopoulos et al, 2017, PMID 28520608). In this curation, data from 18 probands (17 male and 1 female) with unique variants were collected (nonsense, frameshift, splice site, initiator codon, missense) (Van den Hurk et al, 1992, PMID 1598901; Bozbeyoglu et al, 2007, PMID 25390790; Esposito et al, 2011, PMID 21905166; Torriano et al, 2017, PMID 28911202). More data is available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of REP1 (Mitsios et al, 2018, PMID 30627697), functional alteration studies in monocytes and fibroblasts (Seabra et al, 1995, PMID 7592656; Strunnikova et al, 2009, PMID 20027300), zebrafish and mouse models (Krock et al, 2007, PMID 17360570; Tolmachova et al, 2010, PMID 20445111), and the results of gene therapy trials (MacLaren et al, 2014, PMID 24439297). More experimental data to support this gene-disease relationship is available in the literature. In summary, CHM is definitively associated with choroideremia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Retina Gene Curation Expert Panel.