RCBTB1

protein-coding

RCC1 and BTB domain containing protein 1, the group of BTB domain containing

Gene summary

This gene encodes a protein with an N-terminal RCC1 domain and a C-terminal BTB (broad complex, tramtrack and bric-a-brac) domain. In rat, over-expression of this gene in vascular smooth muscle cells induced cellular hypertrophy. In rat, the C-terminus of RCBTB1 interacts with the angiotensin II receptor-1A. In humans, this gene maps to a region of chromosome 13q that is frequently deleted in B-cell chronic lymphocytic leukemia and other lymphoid malignancies. [provided by RefSeq, Jul 2008]

MANE transcript

NM_018191.4

Inheritance

AD, AR

ClinVar variants

P:38U:209B:109

Top phenotype

Retinal dystrophy with or without extraocular anomalies (RDEOA)

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr13:49,531,946-49,585,558

External References & Databases

Ensembl (ENSG00000136144)

Transcript & Mutation Effects

hg38 • Region Span ~53.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

exudative vitreoretinopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019516

Submitter: Ambry Genetics

RCBTB1-related retinopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014955

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.

RCBTB1-related retinopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014955

Submitter: G2P

RCBTB1-related retinopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014955

Submitter: PanelApp Australia

exudative vitreoretinopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019516

Submitter: G2P

reticular dystrophy of the retinal pigment epitheliumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009979

Submitter: Orphanet

RCBTB1-related retinopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014955

Submitter: Ambry Genetics

RCBTB1-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014955

Submitter: ClinGen

RCBTB1 was first reported in relation to autosomal recessive RCBTB1-related retinopathy in 2016 (Coppietiers et al., PMID: 27486781). 13 affected individuals from 6 families were reported in the initial publication. All had retinal disease, with phenotypes ranging from retinitis pigmentosa to chorioretinal macular atrophy. 7 of the individuals from the initial publication had extra-ocular features, primarily affecting the thyroid, ovary, and/or inner ear. The RCBTB1 gene was therefore associated with the disease entity retinal dystrophy with or without extraocular anomalies (MIM# 617175). In total, 12 variants (missense, nonsense, and frameshift) that have been reported in 11 probands in 4 publications (PMIDs: 27486781, 33104391, 35057699, 33624564) are included in this curation. A total of 16 affected individuals were reported in those 4 publications. All had retinopathy, and 8/16 (50%) were reported to have one or more extra-ocular feature, such as symptoms affecting the thyroid, ovary, ear, kidney, and/or neurologic system. 4 of these individuals with reported extra-ocular manifestations were from consanguineous families (3 from the same extended family). No clear pattern of extra-ocular features is evident at this time. Therefore, the Retina GCEP has curated this gene for RCBTB1-related retinopathy, as opposed to a syndromic entity. The mechanism of pathogenicity is reported to be LOF (PMID: 31494449). While not counted in this curation, members of the Retina GCEP have observed at least 6 additional patients affected with retinopathy with potentially causative RCBTB1 variants and no other molecular genetic diagnosis on panel testing (unpublished, Invitae; unpublished, Blueprint). Of note, there is a report of 3 individuals from 2 families with heterozygous RCBTB1 variants with Coats disease and/or FEVR (Wu et al., 2016; PMID: 26908610). However, others report that RCBTB1 does not appear to be enriched in FEVR cohorts as compared to controls (Yang et al., 2021; PMID: 33104391). At this time, there is not sufficient evidence to curate this gene for these phenotypes or autosomal dominant inheritance. This gene-disease association of RCBTB1 with autosomal recessive retinopathy is also supported by experimental evidence including expression studies and in vitro functional assays (PMIDs: 27486781, 34617687). Expression analysis of mRNA shows strong expression in human retina and limited expression in RPE, and RCBTB1 immunoreactivity in the murine retina mainly localized to the inner retina (PMID: 27486781). In addition, RCBTB1 expression reduced in patient RPE compared to control (PMID: 34617687). In cultured RPE cells, RCBTB1 expression reduced in patient RPE compared to control (PMID: 34617687) and morphologic differences (flattened appearance and reduced surface microvillus densities) were observed in cilia in patient-derived RPE cells as compared to control cells (PMID: 34617687). In summary, RCBTB1 is definitively associated with autosomal recessive RCBTB1-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

RCBTB1-related retinopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014955

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Retinal dystrophy with or without extraocular anomalies (RDEOA)AR

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: 27486781

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RCBTB1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 383

not specifiedTotal: 128

RCBTB1-related disorderTotal: 22

RCBTB1-related retinopathyTotal: 12

Retinal dystrophyTotal: 9

Retinitis pigmentosaTotal: 6

RETINAL DYSTROPHY WITH EXTRAOCULAR ANOMALIESTotal: 2

Coats diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018191.4. 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			3 clinvar	97 clinvar	5 clinvar	105
missense		5 clinvar	199 clinvar	5 clinvar	1 clinvar	210
nonsense	5 clinvar	6 clinvar	2 clinvar			13
start loss						0
frameshift	9 clinvar	3 clinvar	1 clinvar			13
splice donor/acceptor (+/-2bp)		10 clinvar	4 clinvar	1 clinvar		15
Total	14	24	209	103	6	356

Highest pathogenic variant AF is 0.00009356021

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 67 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018191.4	RefSeq	NP_060661.3	11	MANE Select
ENST00000378302.7	Ensembl	ENSP00000367552.2	11	MANE Select
NM_001352500.2	RefSeq	NP_001339429.1	11	Standard
NM_001352501.2	RefSeq	NP_001339430.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rcbtb1	Danio rerio	Structure: ocular blood vessel Quality: decreased area abnormal

Gene / Model

Organism

Observed Phenotype

rcbtb1

Danio rerio

Structure: ocular blood vessel

Quality: decreased area

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

chromatin organization
cell cycle

Cellular Component

nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378302
Coding exons: 11
Length: 53638
Individuals with no LoFs: 125703
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125747
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.03	245	295	0.831	0.0000159	3455
Missense (PolyPhen)		57	81.485	0.69951		1008
Synonymous	0.335	115	120	0.961	0.00000743	1032
Loss of Function	2.39	14	27.6	0.508	0.00000137	322

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00049	0.00049	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00014	0.00013	rare
South Asian	0.00014	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in cell cycle regulation by chromatin remodeling. {ECO:0000269|PubMed:11306461}.;

Recessive Scores

pRec: 0.120

Intolerance Scores

LoFtool: 0.462
RVIS EVS: -0.58
RVIS percentile EVS: 18.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.595

Gene Damage Prediction

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