CHM

protein-coding

CHM Rab escort protein, the group of MicroRNA protein coding host genes

Gene summary

This gene encodes component A of the RAB geranylgeranyl transferase holoenzyme. In the dimeric holoenzyme, this subunit binds unprenylated Rab GTPases and then presents them to the catalytic Rab GGTase subunit for the geranylgeranyl transfer reaction. Rab GTPases need to be geranylgeranyled on either one or two cysteine residues in their C-terminus to localize to the correct intracellular membrane. Mutations in this gene are a cause of choroideremia; also known as tapetochoroidal dystrophy (TCD). This X-linked disease is characterized by progressive dystrophy of the choroid, retinal pigment epithelium and retina. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2016]

Previous symbols:

TCD
DXS540

MANE transcript

NM_000390.4

Inheritance

ClinVar variants

P:361U:300B:247

Top phenotype

Choiroideremia

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chrX:85,861,180-86,047,561

External References & Databases

Ensembl (ENSG00000188419)

Transcript & Mutation Effects

hg38 • Region Span ~186.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

choroideremiaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010557

Submitter: Illumina

choroideremiaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010557

Submitter: Natera

choroideremiaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010557

Submitter: ClinGen

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.

choroideremiaSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010557

Submitter: Labcorp Genetics (formerly Invitae)

choroideremiaSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010557

Submitter: Orphanet

choroideremiaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010557

Submitter: G2P

Clinical Genomic Database (CGD)

ChoiroideremiaXL

Manifestation: Ophthalmologic

Intervention: General

Rationale: 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

Refs: 2886237; 1302003; 1598901; 8477262; 7981671; 12827496; 19764077; 20301511; 22965595; 24913019

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHM variants in ClinVar

14 Conditions Cataloged

not providedTotal: 820

ChoroideremiaTotal: 184

CHM-related disordersTotal: 107

not specifiedTotal: 96

Retinal dystrophyTotal: 69

Inborn genetic diseasesTotal: 60

CHM-related disorderTotal: 36

Retinitis pigmentosaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000390.4. 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		2 clinvar	14 clinvar	200 clinvar	9 clinvar	225
missense	2 clinvar	6 clinvar	270 clinvar	34 clinvar	4 clinvar	316
nonsense	94 clinvar	19 clinvar	4 clinvar			117
start loss		3 clinvar				3
frameshift	125 clinvar	37 clinvar	1 clinvar			163
splice donor/acceptor (+/-2bp)	47 clinvar	26 clinvar	11 clinvar			84
Total	268	93	300	234	13	908

Highest pathogenic variant AF is 0.000008969575

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000390.4	RefSeq	NP_000381.1	15	MANE Select
ENST00000357749.7	Ensembl	ENSP00000350386.2	15	MANE Select
NM_001145414.4	RefSeq	NP_001138886.1	5	Standard
NM_001320959.1	RefSeq	NP_001307888.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
chm	Danio rerio	Structure: neuromast hair cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

chm

Danio rerio

Structure: neuromast hair cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gene expression (Transcription)
Vesicle-mediated transport
Membrane Trafficking
Generic Transcription Pathway
Post-translational protein modification

Biological Process

protein targeting to membrane
small GTPase mediated signal transduction
visual perception
protein geranylgeranylation
regulation of apoptotic process

Molecular Function

Rab geranylgeranyltransferase activity
GDP-dissociation inhibitor activity
GTPase activator activity
Rab GTPase binding

Cellular Component

cytosol
Rab-protein geranylgeranyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357749
Coding exons: 15
Length: 186382
Individuals with no LoFs: 125140
Homozygous LoFs: 1
Heterozygous LoFs: 1
Defined: 125142
p: 0.00000799

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.793	195	229	0.852	0.0000161	4300
Missense (PolyPhen)		71	91.524	0.77576		1819
Synonymous	-1.20	95	81.3	1.17	0.00000585	1195
Loss of Function	4.39	1	24.4	0.0410	0.00000189	446

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000037	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.000060	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Substrate-binding subunit of the Rab geranylgeranyltransferase (GGTase) complex. Binds unprenylated Rab proteins and presents the substrate peptide to the catalytic component B composed of RABGGTA and RABGGTB, and remains bound to it after the geranylgeranyl transfer reaction. The component A is thought to be regenerated by transferring its prenylated Rab back to the donor membrane. Besides, a pre-formed complex consisting of CHM and the Rab GGTase dimer (RGGT or component B) can bind to and prenylate Rab proteins; this alternative pathway is proposed to be the predominant pathway for Rab protein geranylgeranylation. {ECO:0000269|PubMed:18532927, ECO:0000269|PubMed:7957092}.;
Disease: DISEASE: Choroideremia (CHM) [MIM:303100]: An X-linked recessive disease characterized by a slowly progressive degeneration of the choroid, photoreceptors, and retinal pigment epithelium. Affected males develop night blindness in their teenage years followed by loss of peripheral vision and complete blindness at middle age. Carrier females are generally asymptomatic but funduscopic examination often shows patchy areas of chorioretinal atrophy. {ECO:0000269|PubMed:19427510, ECO:0000269|PubMed:21905166, ECO:0000269|PubMed:7951216}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.245

Intolerance Scores

RVIS EVS: 0.17
RVIS percentile EVS: 65.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0770

Gene Damage Prediction

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