obesity due to SIM1 deficiency

Summary

obesity due to SIM1 deficiency (MONDO:0018244) is a disease caused by SIM1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: SIM1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 71
• Phenotypes (HPO): 17

Clinical features

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000842	Hyperinsulinemia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001513	Obesity	Very frequent (80-99%)
HP:0002591	Polyphagia	Very frequent (80-99%)
HP:0002615	Hypotension	Very frequent (80-99%)
HP:0005307	Postural hypotension with compensatory tachycardia	Very frequent (80-99%)
HP:0012332	Abnormal autonomic nervous system physiology	Very frequent (80-99%)
HP:0100503	Low levels of vitamin B1	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0002354	Memory impairment	Frequent (30-79%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0001952	Glucose intolerance	Occasional (5-29%)
HP:0001252	Hypotonia	Excluded (0%)
HP:0004322	Short stature	Excluded (0%)
HP:0011968	Feeding difficulties	Excluded (0%)
HP:0012339	Increased resting energy expenditure	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	obesity due to SIM1 deficiency
Mondo ID	MONDO:0018244
Orphanet	369873
UMLS	C5191050
MedGen	1680592
GARD	0021580
Is cancer (heuristic)	no

Data availability: 71 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited obesity › obesity due to SIM1 deficiency

Related subtypes (6): obesity due to prohormone convertase I deficiency, obesity due to pro-opiomelanocortin deficiency, obesity due to congenital leptin deficiency, obesity due to leptin receptor gene deficiency, obesity due to CEP19 deficiency, obesity due to melanocortin 4 receptor 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

71 retrieved; paginated sample, class counts are floors:

41 uncertain significance, 14 benign, 7 conflicting classifications of pathogenicity, 4 benign/likely benign, 3 likely benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1699502	NM_005068.3(SIM1):c.616del (p.Gln206fs)	SIM1	Pathogenic	criteria provided, single submitter
4532010	NM_005068.3(SIM1):c.309del (p.Met102_Tyr103insTer)	SIM1	Pathogenic	criteria provided, single submitter
254101	NM_005068.3(SIM1):c.2119G>C (p.Asp707His)	SIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285978	NM_005068.3(SIM1):c.279C>T (p.Phe93=)	SIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
354677	NM_005068.3(SIM1):c.1569T>C (p.His523=)	SIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
354684	NM_005068.3(SIM1):c.804T>C (p.His268=)	SIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436727	NM_005068.3(SIM1):c.624G>A (p.Val208=)	SIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
729151	NM_005068.3(SIM1):c.383T>C (p.Ile128Thr)	SIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905504	NM_005068.3(SIM1):c.1452C>G (p.Ala484=)	SIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1707529	NM_005068.3(SIM1):c.475T>C (p.Ser159Pro)	SIM1	Uncertain significance	criteria provided, single submitter
354663	NM_005068.3(SIM1):c.*1331T>C	SIM1	Uncertain significance	criteria provided, single submitter
354664	NM_005068.3(SIM1):c.*1278C>T	SIM1	Uncertain significance	criteria provided, single submitter
354665	NM_005068.3(SIM1):c.*1125T>C	SIM1	Uncertain significance	criteria provided, single submitter
354666	NM_005068.3(SIM1):c.*589G>A	SIM1	Uncertain significance	criteria provided, single submitter
354667	NM_005068.3(SIM1):c.*583G>C	SIM1	Uncertain significance	criteria provided, single submitter
354668	NM_005068.3(SIM1):c.*450T>C	SIM1	Uncertain significance	criteria provided, single submitter
354673	NM_005068.3(SIM1):c.*99G>A	SIM1	Uncertain significance	criteria provided, single submitter
354675	NM_005068.3(SIM1):c.2194T>C (p.Leu732=)	SIM1	Uncertain significance	criteria provided, single submitter
354676	NM_005068.3(SIM1):c.2111A>T (p.Gln704Leu)	SIM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
354679	NM_005068.3(SIM1):c.1125C>T (p.Leu375=)	SIM1	Uncertain significance	criteria provided, single submitter
354682	NM_005068.3(SIM1):c.816C>T (p.Cys272=)	SIM1	Uncertain significance	criteria provided, single submitter
354683	NM_005068.3(SIM1):c.804T>G (p.His268Gln)	SIM1	Uncertain significance	criteria provided, single submitter
354687	NM_005068.3(SIM1):c.-58T>C	SIM1	Uncertain significance	criteria provided, single submitter
354689	NM_005068.3(SIM1):c.-181T>A	SIM1	Uncertain significance	criteria provided, single submitter
813617	NM_005068.3(SIM1):c.2267A>G (p.Lys756Arg)	SIM1	Uncertain significance	criteria provided, single submitter
904642	NM_005068.3(SIM1):c.*1369C>A	SIM1	Uncertain significance	criteria provided, single submitter
904716	NM_005068.3(SIM1):c.2108G>A (p.Arg703Gln)	SIM1	Uncertain significance	criteria provided, single submitter
904717	NM_005068.3(SIM1):c.2039C>T (p.Ser680Leu)	SIM1	Uncertain significance	criteria provided, single submitter
904719	NM_005068.3(SIM1):c.1865C>T (p.Ser622Phe)	SIM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
904720	NM_005068.3(SIM1):c.1802A>G (p.Lys601Arg)	SIM1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
SIM1	Definitive	Autosomal dominant	obesity due to SIM1 deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SIM1	Orphanet:171829	6q16 microdeletion syndrome
SIM1	Orphanet:369873	Obesity due to SIM1 deficiency
SIM1	Orphanet:398079	SIM1-related Prader-Willi-like syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SIM1	HGNC:10882	ENSG00000112246	P81133	Single-minded homolog 1	gencc,clinvar
SIM1-AS1	HGNC:40530	ENSG00000228082		SIM1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SIM1	Single-minded homolog 1	Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SIM1	Transcription factor	no		PAS, PAC, SIM_C
SIM1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
renal medulla	1
skeletal muscle tissue of biceps brachii	1
male germ line stem cell (sensu Vertebrata) in testis	1
omental fat pad	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SIM1	76	broad	yes	renal medulla, skeletal muscle tissue of biceps brachii, biceps brachii
SIM1-AS1	54		yes	male germ line stem cell (sensu Vertebrata) in testis, omental fat pad, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SIM1	1,071
SIM1-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SIM1	P81133	60.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ureteric bud development	1	455.5×	0.009	SIM1
nervous system development	1	45.9×	0.044	SIM1
cell differentiation	1	29.1×	0.046	SIM1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	SIM1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SIM1	0	0
SIM1-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	SIM1, SIM1-AS1

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)
SIM1	0	—
SIM1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.