Heterotaxy, visceral, 5, autosomal

Summary

Heterotaxy, visceral, 5, autosomal (MONDO:0700112) is a disease caused by NODAL (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: NODAL (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 132

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	heterotaxy, visceral, 5, autosomal
Mondo ID	MONDO:0700112
OMIM	270100
UMLS	C3495537
MedGen	501198
GARD	0026361
Is cancer (heuristic)	no

Also known as: HTX5 · NODAL visceral heterotaxy · situs inversus viscerum · SIV · visceral heterotaxy caused by mutation in NODAL

Data availability: 132 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › visceral heterotaxy › heterotaxy, visceral, 5, autosomal

Related subtypes (18): right atrial isomerism, situs inversus, heterotaxy, visceral, 1, X-linked, laterality defects, autosomal dominant, heterotaxy, visceral, 2, autosomal, heterotaxy, visceral, 3, autosomal, heterotaxy, visceral, 4, autosomal, heterotaxy, visceral, 6, autosomal, heterotaxy, visceral, 7, autosomal, heterotaxy, visceral, 8, autosomal, dextrocardia, levocardia, heterotaxy, visceral, 9, autosomal, with male infertility, heterotaxy, visceral, 10, autosomal, with male infertility, heterotaxy, visceral, 11, autosomal, with male infertility, heterotaxy, visceral, 12, autosomal, heterotaxy, visceral, 13, autosomal, heterotaxy, visceral, 14, autosomal

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

132 retrieved; paginated sample, class counts are floors:

66 uncertain significance, 29 likely benign, 12 benign, 9 conflicting classifications of pathogenicity, 8 likely pathogenic, 5 pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1460012	NC_000010.10:g.(?72183370)(72201347_?)del	EIF4EBP2	Pathogenic	criteria provided, single submitter
1069992	NM_018055.5(NODAL):c.555del (p.Thr186fs)	NODAL	Pathogenic	criteria provided, single submitter
241245	NM_018055.5(NODAL):c.891+1G>A	NODAL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545545	NM_018055.5(NODAL):c.397C>T (p.Gln133Ter)	NODAL	Pathogenic	criteria provided, single submitter
663619	NM_018055.5(NODAL):c.446del (p.Gly149fs)	NODAL	Pathogenic	criteria provided, single submitter
986360	NM_018055.5(NODAL):c.591C>A (p.Tyr197Ter)	NODAL	Pathogenic	criteria provided, single submitter
1805542	NM_018055.5(NODAL):c.158_165del (p.Pro53fs)	NODAL	Likely pathogenic	criteria provided, single submitter
3255023	NM_018055.5(NODAL):c.735del (p.Gln245fs)	NODAL	Likely pathogenic	criteria provided, single submitter
3366958	NM_018055.5(NODAL):c.408dup (p.Phe137fs)	NODAL	Likely pathogenic	criteria provided, single submitter
423103	NM_018055.5(NODAL):c.824G>A (p.Arg275His)	NODAL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293741	NM_018055.5(NODAL):c.709C>T (p.Arg237Ter)	NODAL	Likely pathogenic	criteria provided, single submitter
545543	NM_018055.5(NODAL):c.700_707del (p.Arg234fs)	NODAL	Likely pathogenic	no assertion criteria provided
545544	NM_018055.5(NODAL):c.194-1G>T	NODAL	Likely pathogenic	no assertion criteria provided
571254	NM_018055.5(NODAL):c.891+2T>A	NODAL	Likely pathogenic	criteria provided, single submitter
1285182	NM_018055.5(NODAL):c.586C>T (p.Leu196Phe)	NODAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1678001	NM_018055.5(NODAL):c.700_723delinsTTGACTTCC (p.Arg234_Pro241delinsLeuThrSer)	NODAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2442204	NM_018055.5(NODAL):c.2T>C (p.Met1Thr)	NODAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
690399	NM_018055.5(NODAL):c.555dup (p.Thr186fs)	NODAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
697481	NM_018055.5(NODAL):c.972G>A (p.Leu324=)	NODAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8268	NM_018055.5(NODAL):c.548G>A (p.Arg183Gln)	NODAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8269	NM_018055.5(NODAL):c.778G>A (p.Gly260Arg)	NODAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877821	NM_018055.5(NODAL):c.819C>G (p.Ala273=)	NODAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95883	NM_018055.5(NODAL):c.904C>T (p.Arg302Cys)	NODAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022610	NC_000010.10:g.(?72179670)(72360658_?)dup	EIF4EBP2	Uncertain significance	criteria provided, single submitter
1010676	NM_018055.5(NODAL):c.53A>G (p.Gln18Arg)	NODAL	Uncertain significance	criteria provided, single submitter
1013953	NM_018055.5(NODAL):c.817G>A (p.Ala273Thr)	NODAL	Uncertain significance	criteria provided, single submitter
1028081	NM_018055.5(NODAL):c.926C>T (p.Pro309Leu)	NODAL	Uncertain significance	criteria provided, single submitter
1423390	NM_018055.5(NODAL):c.869C>T (p.Pro290Leu)	NODAL	Uncertain significance	criteria provided, single submitter
1434807	NM_018055.5(NODAL):c.211C>A (p.Gln71Lys)	NODAL	Uncertain significance	criteria provided, single submitter
1468471	NM_018055.5(NODAL):c.959C>T (p.Pro320Leu)	NODAL	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 8 · 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
NODAL	Definitive	Autosomal dominant	heterotaxy, visceral, 5, autosomal	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NODAL	Orphanet:101063	Situs inversus totalis
NODAL	Orphanet:157769	Situs ambiguus
NODAL	Orphanet:220386	Semilobar holoprosencephaly
NODAL	Orphanet:280195	Septopreoptic holoprosencephaly
NODAL	Orphanet:280200	Microform holoprosencephaly
NODAL	Orphanet:93924	Lobar holoprosencephaly
NODAL	Orphanet:93925	Alobar holoprosencephaly
NODAL	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NODAL	HGNC:7865	ENSG00000156574	Q96S42	Nodal homolog	gencc,clinvar
EIF4EBP2	HGNC:3289	ENSG00000148730	Q13542	Eukaryotic translation initiation factor 4E-binding protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NODAL	Nodal homolog	Essential for mesoderm formation and axial patterning during embryonic development.
EIF4EBP2	Eukaryotic translation initiation factor 4E-binding protein 2	Repressor of translation initiation involved in synaptic plasticity, learning and memory formation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NODAL	Other/Unknown	no		TGF-b_C, TGF-beta-like, TGFb_CS
EIF4EBP2	Other/Unknown	no		EIF4EBP

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac muscle of right atrium	1
left ventricle myocardium	1
upper arm skin	1
buccal mucosa cell	1
epithelium of esophagus	1
esophagus squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NODAL	138	tissue_specific	marker	upper arm skin, cardiac muscle of right atrium, left ventricle myocardium
EIF4EBP2	292	ubiquitous	marker	buccal mucosa cell, esophagus squamous epithelium, epithelium of esophagus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NODAL	1,093
EIF4EBP2	542

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF4EBP2	Q13542	2
NODAL	Q96S42	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of signaling by NODAL	1	951.7×	0.002	NODAL
Signaling by NODAL	1	496.5×	0.002	NODAL

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
polarity specification of proximal/distal axis	1	8426.0×	0.002	NODAL
floor plate morphogenesis	1	8426.0×	0.002	NODAL
axial mesodermal cell fate specification	1	8426.0×	0.002	NODAL
epiblast cell-extraembryonic ectoderm cell signaling	1	8426.0×	0.002	NODAL
trophectodermal cellular morphogenesis	1	4213.0×	0.002	NODAL
negative regulation of cell development	1	4213.0×	0.002	NODAL
left lung morphogenesis	1	4213.0×	0.002	NODAL
negative regulation of chorionic trophoblast cell proliferation	1	4213.0×	0.002	NODAL
neural fold formation	1	2106.5×	0.002	NODAL
inhibition of neuroepithelial cell differentiation	1	2106.5×	0.002	NODAL
formation of anatomical boundary	1	2106.5×	0.002	NODAL
maternal process involved in parturition	1	1685.2×	0.003	NODAL
regulation of gastrulation	1	1404.3×	0.003	NODAL
negative regulation of trophoblast cell migration	1	1203.7×	0.003	NODAL
embryonic process involved in female pregnancy	1	1053.2×	0.003	NODAL
determination of left/right asymmetry in lateral mesoderm	1	936.2×	0.003	NODAL
mesendoderm development	1	936.2×	0.003	NODAL
maternal placenta development	1	766.0×	0.004	NODAL
cell migration involved in gastrulation	1	766.0×	0.004	NODAL
primitive streak formation	1	702.2×	0.004	NODAL
regulation of stem cell population maintenance	1	702.2×	0.004	NODAL
vasculature development	1	561.7×	0.004	NODAL
nodal signaling pathway	1	561.7×	0.004	NODAL
digestive tract morphogenesis	1	495.6×	0.005	NODAL
negative regulation of androgen receptor signaling pathway	1	468.1×	0.005	NODAL
negative regulation of translational initiation	1	443.5×	0.005	EIF4EBP2
embryonic placenta development	1	383.0×	0.005	NODAL
positive regulation of cell-cell adhesion	1	383.0×	0.005	NODAL
TOR signaling	1	383.0×	0.005	EIF4EBP2
cell surface receptor protein serine/threonine kinase signaling pathway	1	366.4×	0.005	NODAL

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
NODAL	0	0
EIF4EBP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	NODAL, EIF4EBP2

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)
NODAL	0	—
EIF4EBP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.