Renal hypomagnesemia 4

Summary

Renal hypomagnesemia 4 (MONDO:0012717) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 143

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	renal hypomagnesemia 4
Mondo ID	MONDO:0012717
MeSH	C567127
OMIM	611718
DOID	DOID:0060882
UMLS	C2673648
MedGen	388692
GARD	0024886
Is cancer (heuristic)	no

Also known as: EGF familial primary hypomagnesemia · EGF primary hypomagnesemia · familial primary hypomagnesemia caused by mutation in EGF · HOMG4 · hypomagnesemia 4, renal · primary hypomagnesemia caused by mutation in EGF · renal hypomagnesemia type 4

Data availability: 143 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn metal metabolism disorder › familial primary hypomagnesemia › familial primary hypomagnesemia with normocalcuria › familial primary hypomagnesemia with normocalciuria and normocalcemia › renal hypomagnesemia 4

Related subtypes (2): renal hypomagnesemia 6, hypomagnesemia, seizures, and intellectual disability

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

143 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 24 benign, 20 conflicting classifications of pathogenicity, 16 benign/likely benign, 15 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16614	NM_001963.6(EGF):c.3209C>T (p.Pro1070Leu)	EGF	Pathogenic	no assertion criteria provided
347236	NM_001963.6(EGF):c.1491T>C (p.His497=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347240	NM_001963.6(EGF):c.1818T>C (p.His606=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347256	NM_001963.6(EGF):c.3162C>G (p.Ala1054=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347258	NM_001963.6(EGF):c.3371-4A>G	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347261	NM_001963.6(EGF):c.3530G>C (p.Gly1177Ala)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
721901	NM_001963.6(EGF):c.57T>C (p.Ser19=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
730986	NM_001963.6(EGF):c.1137C>T (p.Tyr379=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
762136	NM_001963.6(EGF):c.2940C>T (p.His980=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
762429	NM_001963.6(EGF):c.2760G>A (p.Glu920=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
778314	NM_001963.6(EGF):c.1602G>A (p.Lys534=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
781980	NM_001963.6(EGF):c.3292-7T>C	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900057	NM_001963.6(EGF):c.1821A>G (p.Pro607=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900058	NM_001963.6(EGF):c.1851A>G (p.Thr617=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901154	NM_001963.6(EGF):c.1097G>A (p.Gly366Asp)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901215	NM_001963.6(EGF):c.2337G>A (p.Thr779=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901701	NM_001963.6(EGF):c.1404C>T (p.Asp468=)	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902667	NM_001963.6(EGF):c.3006-11T>G	EGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347243	NM_001963.6(EGF):c.2088T>C (p.Tyr696=)	LOC126807134	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
739998	NM_001963.6(EGF):c.2362C>T (p.Leu788=)	LOC126807134	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901213	NM_001963.6(EGF):c.2223A>G (p.Gly741=)	LOC126807134	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1350941	NM_001963.6(EGF):c.887A>C (p.Lys296Thr)	EGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1357481	NM_001963.6(EGF):c.1864C>T (p.Arg622Ter)	EGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1368025	NM_001963.6(EGF):c.464G>A (p.Ser155Asn)	EGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1384032	NM_001963.6(EGF):c.1052G>A (p.Arg351Gln)	EGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1403287	NM_001963.6(EGF):c.638G>A (p.Arg213Gln)	EGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1410240	NM_001963.6(EGF):c.2378A>T (p.Glu793Val)	EGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1426041	NM_001963.6(EGF):c.1480C>T (p.Arg494Ter)	EGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1427951	NM_001963.6(EGF):c.1354G>A (p.Val452Ile)	EGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1507059	NM_001963.6(EGF):c.1919A>G (p.Asp640Gly)	EGF	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
EGF	Supportive	Autosomal dominant	familial primary hypomagnesemia with normocalciuria and normocalcemia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EGF	Orphanet:210159	Adult hepatocellular carcinoma
EGF	Orphanet:620368	EGF-related primary hypomagnesemia with intellectual disability

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EGF	HGNC:3229	ENSG00000138798	P01133	Pro-epidermal growth factor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EGF	Pro-epidermal growth factor	EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EGF	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
hindlimb stylopod muscle	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EGF	215	broad	marker	renal medulla, body of pancreas, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EGF	8,267

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EGF	P01133	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. Enrichment computed across 1 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
PLCG1 events in ERBB2 signaling	1	2855.0×	0.004	EGF
Inhibition of Signaling by Overexpressed EGFR	1	1268.9×	0.004	EGF
EGFR interacts with phospholipase C-gamma	1	1142.0×	0.004	EGF
NFE2L2 regulating tumorigenic genes	1	951.7×	0.004	EGF
ERBB2 Activates PTK6 Signaling	1	815.7×	0.004	EGF
GRB2 events in EGFR signaling	1	761.3×	0.004	EGF
SHC1 events in EGFR signaling	1	713.8×	0.004	EGF
Constitutive Signaling by EGFRvIII	1	713.8×	0.004	EGF
ERBB2 Regulates Cell Motility	1	713.8×	0.004	EGF
PI3K events in ERBB2 signaling	1	671.8×	0.004	EGF
Signaling by ERBB2 ECD mutants	1	671.8×	0.004	EGF
GAB1 signalosome	1	634.4×	0.004	EGF
GRB2 events in ERBB2 signaling	1	634.4×	0.004	EGF
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	601.0×	0.004	EGF
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	571.0×	0.004	EGF
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	543.8×	0.004	EGF
SHC1 events in ERBB2 signaling	1	475.8×	0.004	EGF
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.004	EGF
Signaling by ERBB2 TMD/JMD mutants	1	475.8×	0.004	EGF
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	456.8×	0.004	EGF
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	1	439.2×	0.004	EGF
Signaling by ERBB2 KD Mutants	1	423.0×	0.004	EGF
Downregulation of ERBB2 signaling	1	380.7×	0.004	EGF
Signaling by ERBB2	1	346.1×	0.004	EGF
EGFR downregulation	1	346.1×	0.004	EGF
Signaling by EGFR	1	326.3×	0.004	EGF
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	278.5×	0.005	EGF
Signaling by ERBB4	1	271.9×	0.005	EGF
Extra-nuclear estrogen signaling	1	170.4×	0.007	EGF
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.009	EGF

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
positive regulation of hyaluronan biosynthetic process	1	4213.0×	0.002	EGF
positive regulation of cerebellar granule cell precursor proliferation	1	3370.4×	0.002	EGF
negative regulation of secretion	1	3370.4×	0.002	EGF
negative regulation of cholesterol efflux	1	2808.7×	0.002	EGF
positive regulation of epithelial tube formation	1	2808.7×	0.002	EGF
regulation of calcium ion import	1	2106.5×	0.002	EGF
positive regulation of peptidyl-threonine phosphorylation	1	1872.4×	0.002	EGF
ubiquitin-dependent endocytosis	1	1872.4×	0.002	EGF
ERBB2-EGFR signaling pathway	1	1685.2×	0.002	EGF
positive regulation of protein localization to early endosome	1	1685.2×	0.002	EGF
regulation of protein localization to cell surface	1	1685.2×	0.002	EGF
cerebellar granule cell precursor proliferation	1	1532.0×	0.002	EGF
regulation of receptor signaling pathway via JAK-STAT	1	1404.3×	0.002	EGF
positive regulation of DNA binding	1	1203.7×	0.002	EGF
mammary gland alveolus development	1	991.3×	0.002	EGF
positive regulation of phosphorylation	1	842.6×	0.003	EGF
negative regulation of epidermal growth factor receptor signaling pathway	1	766.0×	0.003	EGF
branching morphogenesis of an epithelial tube	1	732.7×	0.003	EGF
positive regulation of receptor internalization	1	702.2×	0.003	EGF
positive regulation of ubiquitin-dependent protein catabolic process	1	561.7×	0.003	EGF
positive regulation of mitotic nuclear division	1	543.6×	0.003	EGF
ERK1 and ERK2 cascade	1	318.0×	0.005	EGF
epithelial cell proliferation	1	312.1×	0.005	EGF
positive regulation of endothelial cell migration	1	251.5×	0.006	EGF
epidermal growth factor receptor signaling pathway	1	247.8×	0.006	EGF
positive regulation of endothelial cell proliferation	1	230.8×	0.006	EGF
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.009	EGF
positive regulation of MAPK cascade	1	80.6×	0.016	EGF
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.016	EGF
ubiquitin-dependent protein catabolic process	1	74.2×	0.016	EGF

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EGF	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EGF	5	Binding:5

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	1	EGF

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EGF	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.