autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency

Summary

autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency (MONDO:0014710) is a disease caused by RORC (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RORC (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 301

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency
Mondo ID	MONDO:0014710
OMIM	616622
Orphanet	477857
DOID	DOID:0111940
UMLS	C5567647
MedGen	1799070
GARD	0017861
Is cancer (heuristic)	no

Also known as: autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency caused by mutation in RORC · IMD42 · immunodeficiency 42 · immunodeficiency type 42 · RORC autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency

Data availability: 301 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › inherited susceptibility to mycobacterial diseases › autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency

Related subtypes (13): immunodeficiency 27A, Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency, Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency, autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency, X-linked Mendelian susceptibility to mycobacterial diseases, Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to a complete deficiency, Mendelian susceptibility to mycobacterial diseases due to a partial deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

301 retrieved; paginated sample, class counts are floors:

155 likely benign, 115 uncertain significance, 12 benign, 9 pathogenic, 5 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
217445	NM_005060.4(RORC):c.113C>T (p.Ser38Leu)	RORC	Pathogenic	no assertion criteria provided
217446	NM_005060.4(RORC):c.985C>T (p.Gln329Ter)	RORC	Pathogenic	no assertion criteria provided
217447	NM_005060.4(RORC):c.1321C>T (p.Gln441Ter)	RORC	Pathogenic	no assertion criteria provided
2697193	NM_005060.4(RORC):c.292C>T (p.Arg98Ter)	RORC	Pathogenic	criteria provided, single submitter
2860649	NM_005060.4(RORC):c.682C>T (p.Arg228Ter)	RORC	Pathogenic	criteria provided, single submitter
3722087	NM_005060.4(RORC):c.908del (p.Glu303fs)	RORC	Pathogenic	criteria provided, single submitter
4720711	NM_005060.4(RORC):c.990C>A (p.Tyr330Ter)	RORC	Pathogenic	criteria provided, single submitter
4725563	NM_005060.4(RORC):c.205_208del (p.Arg69fs)	RORC	Pathogenic	criteria provided, single submitter
4734088	NM_005060.4(RORC):c.811G>T (p.Glu271Ter)	RORC	Pathogenic	criteria provided, single submitter
1068314	NM_005060.4(RORC):c.934-1G>A	RORC	Likely pathogenic	criteria provided, single submitter
2585221	NM_005060.4(RORC):c.1165C>T (p.Arg389Ter)	RORC	Likely pathogenic	criteria provided, single submitter
4813333	NM_005060.4(RORC):c.991G>A (p.Val331Met)	RORC	Likely pathogenic	criteria provided, single submitter
2883223	NM_005060.4(RORC):c.442A>G (p.Thr148Ala)	RORC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3611365	NM_005060.4(RORC):c.695G>A (p.Arg232His)	RORC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475712	NM_005060.4(RORC):c.28C>T (p.Arg10Ter)	RORC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
948680	NM_005060.4(RORC):c.374G>A (p.Arg125Gln)	RORC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
966608	NM_005060.4(RORC):c.38G>A (p.Arg13Gln)	RORC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2425291	NC_000001.10:g.(?151801885)(152287932_?)dup	C2CD4D	Uncertain significance	criteria provided, single submitter
1445481	NC_000001.10:g.(?149895434)(156851434_?)dup	ECM1	Uncertain significance	criteria provided, single submitter
1002461	NM_005060.4(RORC):c.880C>T (p.Arg294Trp)	RORC	Uncertain significance	criteria provided, single submitter
1009678	NM_005060.4(RORC):c.1427G>C (p.Cys476Ser)	RORC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1010138	NM_005060.4(RORC):c.905G>A (p.Arg302Gln)	RORC	Uncertain significance	criteria provided, single submitter
1013992	NM_005060.4(RORC):c.188C>T (p.Ala63Val)	RORC	Uncertain significance	criteria provided, single submitter
1020582	NM_005060.4(RORC):c.1468C>T (p.His490Tyr)	RORC	Uncertain significance	criteria provided, single submitter
1028332	NM_005060.4(RORC):c.1535C>G (p.Ser512Ter)	RORC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1035931	NM_005060.4(RORC):c.382C>G (p.Gln128Glu)	RORC	Uncertain significance	criteria provided, single submitter
1040267	NM_005060.4(RORC):c.623G>A (p.Arg208Gln)	RORC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1057995	NM_005060.4(RORC):c.770G>A (p.Arg257His)	RORC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1060567	NM_005060.4(RORC):c.1288C>T (p.Arg430Trp)	RORC	Uncertain significance	criteria provided, single submitter
1062297	NM_005060.4(RORC):c.64C>T (p.His22Tyr)	RORC	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RORC	Strong	Autosomal recessive	autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RORC	Orphanet:477857	Mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency
ECM1	Orphanet:530	Lipoid proteinosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RORC	HGNC:10260	ENSG00000143365	P51449	Nuclear receptor ROR-gamma	gencc,clinvar
ECM1	HGNC:3153	ENSG00000143369	Q16610	Extracellular matrix protein 1	clinvar
C2CD4D	HGNC:37210	ENSG00000225556	B7Z1M9	C2 calcium-dependent domain-containing protein 4D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RORC	Nuclear receptor ROR-gamma	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.
ECM1	Extracellular matrix protein 1	Involved in endochondral bone formation as negative regulator of bone mineralization.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	128.6×	0.016
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RORC	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
ECM1	Other/Unknown	no		ECM1, Serum_albumin-like
C2CD4D	Other/Unknown	no		C2_dom, C2_domain_sf, C2C4C/C2C4D

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1
buccal mucosa cell	1
lower esophagus mucosa	1
pharyngeal mucosa	1
C1 segment of cervical spinal cord	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RORC	209	broad	marker	gastrocnemius, male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle
ECM1	253	ubiquitous	marker	lower esophagus mucosa, buccal mucosa cell, pharyngeal mucosa
C2CD4D	112		yes	skin of leg, zone of skin, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ECM1	1,835
RORC	1,594
C2CD4D	295

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RORC	P51449	161

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ECM1	Q16610	69.05
C2CD4D	B7Z1M9	66.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX3 Regulates Immune Response and Cell Migration	1	951.7×	0.014	RORC
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	1	237.9×	0.021	RORC
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	1	203.9×	0.021	RORC
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	146.4×	0.022	RORC
Nuclear Receptor transcription pathway	1	100.2×	0.026	RORC
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.042	RORC
Platelet degranulation	1	43.9×	0.042	ECM1
Signaling by Interleukins	1	32.1×	0.050	RORC
Cytokine Signaling in Immune system	1	20.4×	0.070	RORC
RNA Polymerase II Transcription	1	11.3×	0.113	RORC
Gene expression (Transcription)	1	8.9×	0.129	RORC
Generic Transcription Pathway	1	7.5×	0.139	RORC
Immune System	1	6.5×	0.148	RORC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of type 2 immune response	1	8426.0×	0.003	ECM1
negative regulation of peptidase activity	1	4213.0×	0.003	ECM1
tolerance induction in gut-associated lymphoid tissue	1	2106.5×	0.003	RORC
cellular response to sterol	1	1685.2×	0.003	RORC
T-helper cell differentiation	1	1685.2×	0.003	RORC
regulation of steroid metabolic process	1	1203.7×	0.003	RORC
T-helper 17 cell differentiation	1	1203.7×	0.003	RORC
regulation of T cell migration	1	1203.7×	0.003	ECM1
regulatory T cell differentiation	1	1053.2×	0.003	RORC
Peyer’s patch development	1	1053.2×	0.003	RORC
negative regulation of cytokine-mediated signaling pathway	1	936.2×	0.003	ECM1
endochondral bone growth	1	842.6×	0.003	ECM1
negative regulation of thymocyte apoptotic process	1	842.6×	0.003	RORC
regulation of fat cell differentiation	1	648.1×	0.004	RORC
positive regulation of circadian rhythm	1	601.9×	0.004	RORC
chondrocyte development	1	468.1×	0.004	ECM1
negative regulation of bone mineralization	1	468.1×	0.004	ECM1
lymph node development	1	401.2×	0.005	RORC
regulation of bone mineralization	1	366.4×	0.005	ECM1
biomineral tissue development	1	324.1×	0.005	ECM1
regulation of glucose metabolic process	1	280.9×	0.006	RORC
adipose tissue development	1	200.6×	0.008	RORC
regulation of transcription by RNA polymerase II	2	11.7×	0.011	RORC, ECM1
circadian regulation of gene expression	1	117.0×	0.011	RORC
positive regulation of endothelial cell proliferation	1	115.4×	0.011	ECM1
ossification	1	113.9×	0.011	ECM1
xenobiotic metabolic process	1	74.6×	0.017	RORC
positive regulation of angiogenesis	1	57.7×	0.021	ECM1
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.032	ECM1
angiogenesis	1	31.2×	0.036	ECM1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RORC	DIGOXIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RORC	9	4
ECM1	0	0
C2CD4D	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIGOXIN	4	RORC
TRETINOIN	4	RORC
ALITRETINOIN	4	RORC
CHOLESTEROL	2	RORC
URSOLIC ACID	2	RORC
BETULINIC ACID	1	RORC
GSK2981278	1	RORC
CINTIRORGON	1	RORC
BMS-986251	1	RORC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RORC	758	Binding:707, Functional:50, Unclassified:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RORC	758

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

9 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
DIGOXIN	4	RORC
TRETINOIN	4	RORC
ALITRETINOIN	4	RORC
CHOLESTEROL	2	RORC
URSOLIC ACID	2	RORC
BETULINIC ACID	1	RORC
GSK2981278	1	RORC
CINTIRORGON	1	RORC
BMS-986251	1	RORC

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RORC
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ECM1, C2CD4D

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ECM1	0	—
C2CD4D	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.