RORC

RAR related orphan receptor C, the group of RAR related orphan receptors

Basic information

Region (hg38): 1:151806070-151831845

Links

ENSG00000143365 ∙ ∙ OMIM:602943 ∙ HGNC:10260 ∙ Uniprot:P51449 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency (Moderate), mode of inheritance: AR
• autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency (Supportive), mode of inheritance: AR
• autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 42	AR	Allergy/Immunology/Infectious	Indiviiduals have been described as having increased susceptibility to mycobacterial and candidal infections, as well as disseminated mycobacterial infections after BCG vacciination, and awareness may allow preventive measures, and early and aggressive treatment of infections	Allergy/Immunology/Infectious	26160376

ClinVar

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

• Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency (236 variants)
• not specified (19 variants)
• Inborn genetic diseases (11 variants)
• not provided (5 variants)
• RORC-related condition (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RORC 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			3	68	6	77
missense			108	3	2	113
nonsense	1	1	1	1		4
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)		1	2			3
splice region			3	6	1	10
non coding			1	29	19	49
Total	1	2	115	101	27

Variants in RORC

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

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

Position	Type	Phenotype	Significance	ClinVar
1-151807484-C-A		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Oct 07, 2018)
1-151807494-G-C		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Mar 23, 2022)
1-151807498-C-T		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Mar 26, 2022)
1-151807499-G-A		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Benign (Dec 06, 2023)
1-151807517-C-T		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency • RORC-related disorder	Likely benign (Dec 19, 2023)
1-151807539-G-A		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Sep 01, 2022)
1-151807540-C-T		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Mar 13, 2022)
1-151807541-G-A		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Likely benign (Aug 03, 2021)
1-151807541-G-T		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Apr 30, 2020)
1-151807544-T-C		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Likely benign (Oct 24, 2022)
1-151807550-C-T		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Likely benign (Apr 06, 2023)
1-151807552-C-T		not specified • Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Aug 16, 2022)
1-151807561-G-A		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Aug 27, 2021)
1-151807565-G-A		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Likely benign (May 15, 2022)
1-151807573-A-T		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Sep 10, 2018)
1-151807582-G-C		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Oct 13, 2022)
1-151807602-C-G		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Jul 19, 2022)
1-151807622-C-G		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Uncertain significance (Dec 11, 2023)
1-151807623-T-C		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Benign (Jan 29, 2024)
1-151807625-G-C		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Likely benign (Oct 28, 2021)
1-151807628-T-G		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Likely benign (Jan 22, 2023)
1-151807637-G-C		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Likely benign (Sep 20, 2021)
1-151807641-T-C		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Likely benign (Oct 28, 2023)
1-151807653-G-T		Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	Likely benign (Sep 20, 2022)
1-151807701-C-T		not specified	Benign (Nov 12, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RORC	protein_coding	protein_coding	ENST00000318247	11	25802

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000151	125215	0	532	125747	0.00212

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.29	192	304	0.631	0.0000183	3340
Missense in Polyphen		26	100.72	0.25813		1121
Synonymous	-0.508	127	120	1.06	0.00000681	1020
Loss of Function	4.86	1	29.5	0.0339	0.00000176	299

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00156	0.00156
Ashkenazi Jewish	0.000397	0.000397
East Asian	0.00	0.00
Finnish	0.00106	0.000971
European (Non-Finnish)	0.00371	0.00371
Middle Eastern	0.00	0.00
South Asian	0.00131	0.00131
Other	0.00147	0.00147

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of cellular differentiation, immunity, peripheral circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism (PubMed:19381306, PubMed:19965867, PubMed:22789990, PubMed:26160376, PubMed:20203100). Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively (PubMed:19965867, PubMed:22789990). Recruits distinct combinations of cofactors to target gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, ARNTL/BMAL1 and NR1D1 in peripheral tissues and in a tissue- selective manner. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORC- mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A (PubMed:19965867). Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA as positive or negative modulator of expression of genes encoding phase I and Phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as SULT1E1. Also plays also a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC and PCK1 (PubMed:19965867). Regulates the rhythmic expression of PROX1 and promotes its nuclear localization (PubMed:19381306, PubMed:19965867, PubMed:22789990, PubMed:26160376, PubMed:20203100). Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity (PubMed:26160376). {ECO:0000250|UniProtKB:P51450, ECO:0000269|PubMed:19381306, ECO:0000269|PubMed:19965867, ECO:0000269|PubMed:20203100, ECO:0000269|PubMed:22789990, ECO:0000269|PubMed:26160376}.
• Disease: DISEASE: Immunodeficiency 42 (IMD42) [MIM:616622]: An autosomal recessive primary immunodeficiency characterized by increased susceptibility to concomitant candidiasis and mycobacteriosis. Candidiasis is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida. Mycobacteriosis is characterized by infections caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine, environmental non- tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. IMD42 patients vaccinated with BCG are particularly at risk for developing disseminated mycobacterial infections. {ECO:0000269|PubMed:26160376}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Circadian rhythm - Homo sapiens (human);Inflammatory bowel disease (IBD) - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);NHR;Nuclear Receptors;Interleukin-4 and 13 signaling;Transcriptional regulation by RUNX3;RUNX3 Regulates Immune Response and Cell Migration;Gene expression (Transcription);Transcriptional regulation by RUNX3;Generic Transcription Pathway;Nuclear Receptor transcription pathway;RNA Polymerase II Transcription (Consensus)

Recessive Scores

• pRec: 0.0949

Intolerance Scores

• loftool: 0.0138
• rvis_EVS: 0.04
• rvis_percentile_EVS: 57.15

Haploinsufficiency Scores

• pHI: 0.675
• hipred: Y
• hipred_score: 0.701
• ghis: 0.452

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.994

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rorc
• Phenotype: 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); immune system phenotype; digestive/alimentary phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;transcription initiation from RNA polymerase II promoter;xenobiotic metabolic process;regulation of glucose metabolic process;regulation of steroid metabolic process;cytokine-mediated signaling pathway;intracellular receptor signaling pathway;circadian regulation of gene expression;cellular response to sterol;positive regulation of circadian rhythm;steroid hormone mediated signaling pathway;regulation of fat cell differentiation;positive regulation of transcription, DNA-templated;adipose tissue development;regulation of transcription involved in cell fate commitment;T-helper 17 cell differentiation
• Cellular component: nucleus;nucleoplasm;nuclear body
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;transcription coactivator binding;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA-binding transcription factor activity;steroid hormone receptor activity;nuclear receptor activity;protein binding;oxysterol binding;zinc ion binding;ligand-activated transcription factor activity