Intestinal hypomagnesemia 1

Summary

Intestinal hypomagnesemia 1 (MONDO:0011176) is a disease caused by variants in TRPM6 and TRPV6, with 3 cohort genes and 1 clinical trial. The dominant Reactome pathway is TRP channels (3 cohort genes).

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal genes: TRPM6 (GenCC Strong), TRPV6 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 423
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	intestinal hypomagnesemia 1
Mondo ID	MONDO:0011176
MeSH	C566593
OMIM	602014
Orphanet	30924
DOID	DOID:0060883
SNOMED CT	190856003
UMLS	C1865974
MedGen	355596
GARD	0013072
Is cancer (heuristic)	no

Also known as: familial primary hypomagnesemia caused by mutation in TRPM6 · HOMG1 · HSH · hypomagnesemia 1, intestinal · hypomagnesemia caused by selective magnesium malabsorption · hypomagnesemia intestinal type 1 · hypomagnesemic tetany · intestinal hypomagnesemia type 1 · intestinal hypomagnesemia with secondary hypocalcemia · PHSH · primary hypomagnesemia caused by mutation in TRPM6 · primary hypomagnesemia with secondary hypocalcemia · TRPM6 familial primary hypomagnesemia · TRPM6 primary hypomagnesemia

Data availability: 423 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 › intestinal hypomagnesemia 1

Related subtypes (2): isolated autosomal dominant hypomagnesemia, Glaudemans type, familial primary hypomagnesemia with normocalciuria and normocalcemia

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

423 retrieved; paginated sample, class counts are floors:

276 uncertain significance, 37 conflicting classifications of pathogenicity, 27 pathogenic, 24 likely pathogenic, 21 benign, 21 likely benign, 14 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
998083	NM_017672.6(TRPM7):c.3+1G>C	LOC128092252	Pathogenic	no assertion criteria provided
1030275	NM_017662.5(TRPM6):c.841+1G>A	TRPM6	Pathogenic	criteria provided, multiple submitters, no conflicts
1064591	NM_017662.5(TRPM6):c.1308+7T>G	TRPM6	Pathogenic	criteria provided, multiple submitters, no conflicts
1173100	NM_017662.5(TRPM6):c.4057C>T (p.Arg1353Ter)	TRPM6	Pathogenic	criteria provided, single submitter
1173101	NM_017662.5(TRPM6):c.3094+2T>C	TRPM6	Pathogenic	criteria provided, single submitter
1179128	NM_017662.5(TRPM6):c.3694del (p.Gln1232fs)	TRPM6	Pathogenic	criteria provided, multiple submitters, no conflicts
1325240	NM_017662.5(TRPM6):c.5314C>T (p.Arg1772Ter)	TRPM6	Pathogenic	criteria provided, multiple submitters, no conflicts
1526207	NM_017662.5(TRPM6):c.2782C>T (p.Arg928Ter)	TRPM6	Pathogenic	criteria provided, single submitter
1705325	NM_017662.5(TRPM6):c.1308+1G>T	TRPM6	Pathogenic	criteria provided, single submitter
1706553	NM_017662.5(TRPM6):c.1437C>A (p.Tyr479Ter)	TRPM6	Pathogenic	criteria provided, single submitter
1709626	NM_017662.5(TRPM6):c.3158A>G (p.Tyr1053Cys)	TRPM6	Pathogenic	criteria provided, single submitter
218238	NM_017662.5(TRPM6):c.2667+1G>A	TRPM6	Pathogenic	criteria provided, single submitter
2572474	NM_017662.5(TRPM6):c.3643del (p.Ser1215fs)	TRPM6	Pathogenic	criteria provided, single submitter
2572490	NM_017662.5(TRPM6):c.2958del (p.Ile986fs)	TRPM6	Pathogenic	criteria provided, single submitter
3575	NM_017662.5(TRPM6):c.1769C>G (p.Ser590Ter)	TRPM6	Pathogenic	no assertion criteria provided
3577	NM_017662.5(TRPM6):c.1280del (p.His427fs)	TRPM6	Pathogenic	no assertion criteria provided
3578	NM_017662.5(TRPM6):c.3779_3791del (p.Glu1260fs)	TRPM6	Pathogenic	no assertion criteria provided
3579	NM_017662.5(TRPM6):c.2208del (p.Arg736fs)	TRPM6	Pathogenic	no assertion criteria provided
3580	NM_017662.5(TRPM6):c.2009+1G>A	TRPM6	Pathogenic	no assertion criteria provided
3581	NM_017662.5(TRPM6):c.1420C>T (p.Arg474Ter)	TRPM6	Pathogenic	no assertion criteria provided
3582	NM_017662.5(TRPM6):c.166C>T (p.Arg56Ter)	TRPM6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3583	NM_017662.5(TRPM6):c.1010+5G>C	TRPM6	Pathogenic	no assertion criteria provided
3584	TRPM6, IVS23AS, A-G, -68	TRPM6	Pathogenic	no assertion criteria provided
3585	NM_017662.5(TRPM6):c.422C>T (p.Ser141Leu)	TRPM6	Pathogenic	no assertion criteria provided
3597542	NM_017662.5(TRPM6):c.4287C>A (p.Cys1429Ter)	TRPM6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3597633	NM_017662.5(TRPM6):c.1018C>T (p.Arg340Ter)	TRPM6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
427900	NM_017662.5(TRPM6):c.3357C>A (p.Cys1119Ter)	TRPM6	Pathogenic	criteria provided, single submitter
4293110	NM_017662.5(TRPM6):c.5742C>A (p.Tyr1914Ter)	TRPM6	Pathogenic	criteria provided, single submitter
4686645	NM_017662.5(TRPM6):c.1966dup (p.His656fs)	TRPM6	Pathogenic	criteria provided, single submitter
974783	NM_017672.6(TRPM7):c.3137G>A (p.Gly1046Asp)	TRPM7	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
TRPM6	Strong	Autosomal recessive	intestinal hypomagnesemia 1	3
TRPV6	Strong	Autosomal recessive	intestinal hypomagnesemia 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPM6	Orphanet:30924	Primary hypomagnesemia with secondary hypocalcemia
TRPV6	Orphanet:417	Neonatal severe primary hyperparathyroidism
TRPV6	Orphanet:676	Autosomal dominant hereditary chronic pancreatitis
TRPM7	Orphanet:140957	Autosomal dominant macrothrombocytopenia
TRPM7	Orphanet:90020	Parkinson-dementia complex of Guam

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
TRPM6	HGNC:17995	ENSG00000119121	Q9BX84	Transient receptor potential cation channel subfamily M member 6	gencc,clinvar
TRPV6	HGNC:14006	ENSG00000165125	Q9H1D0	Transient receptor potential cation channel subfamily V member 6	gencc
TRPM7	HGNC:17994	ENSG00000092439	Q96QT4	Transient receptor potential cation channel subfamily M member 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPM6	Transient receptor potential cation channel subfamily M member 6	Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain.
TRPV6	Transient receptor potential cation channel subfamily V member 6	Calcium selective cation channel that mediates Ca(2+) uptake in various tissues, including the intestine.
TRPM7	Transient receptor potential cation channel subfamily M member 7	Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	2	18.5×	0.008
Ion channel	1	37.2×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPM6	Kinase	yes		a-kinase_dom, Ion_trans_dom, Kinase-like_dom_sf
TRPV6	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TRPV5/TRPV6
TRPM7	Kinase	yes		a-kinase_dom, Kinase-like_dom_sf, TRPM7_a-kinase_dom

Expression context

Cohort genes with no expression data: 0.

3 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
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
body of pancreas	1
duodenum	1
pancreas	1
calcaneal tendon	1
cardiac muscle of right atrium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPM6	178	tissue_specific	marker	colonic mucosa, mucosa of sigmoid colon, jejunal mucosa
TRPV6	125	tissue_specific	marker	body of pancreas, pancreas, duodenum
TRPM7	247	ubiquitous	marker	left ventricle myocardium, calcaneal tendon, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRPM7	1,995
TRPV6	1,197
TRPM6	950

Intra-cohort edges

A	B	Sources
TRPM6	TRPM7	string_interaction
TRPM6	TRPV6	string_interaction
TRPM7	TRPV6	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPV6	Q9H1D0	24

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRPM7	Q96QT4	69.90
TRPM6	Q9BX84	65.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TRP channels	3	407.9×	1e-08	TRPM6, TRPV6, TRPM7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
calcium ion transmembrane transport	3	210.7×	2e-06	TRPM6, TRPV6, TRPM7
calcium ion transport	3	181.2×	2e-06	TRPM6, TRPV6, TRPM7
monoatomic cation transmembrane transport	2	416.1×	5e-05	TRPM6, TRPM7
calcium-dependent cell-matrix adhesion	1	2808.7×	0.001	TRPM7
parathyroid hormone secretion	1	2808.7×	0.001	TRPV6
magnesium ion transmembrane transport	1	1404.3×	0.002	TRPM6
intracellular magnesium ion homeostasis	1	936.2×	0.003	TRPM7
magnesium ion homeostasis	1	624.1×	0.004	TRPM7
zinc ion transport	1	510.7×	0.005	TRPM7
magnesium ion transport	1	401.2×	0.005	TRPM7
necroptotic process	1	351.1×	0.005	TRPM7
regulation of calcium ion-dependent exocytosis	1	312.1×	0.006	TRPV6
protein tetramerization	1	208.1×	0.008	TRPM6
actomyosin structure organization	1	187.2×	0.008	TRPM7
calcium ion import across plasma membrane	1	181.2×	0.008	TRPV6
calcium ion homeostasis	1	147.8×	0.009	TRPV6
response to calcium ion	1	106.0×	0.012	TRPV6
protein homotetramerization	1	79.1×	0.015	TRPM7
response to toxic substance	1	70.2×	0.016	TRPM6
protein autophosphorylation	1	48.4×	0.022	TRPM7
protein phosphorylation	1	22.6×	0.044	TRPM7

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
TRPM6	TOFACITINIB
TRPV6	ECONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPV6	3	4
TRPM6	2	4
TRPM7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TOFACITINIB	4	TRPM6
ECONAZOLE	4	TRPV6
TG100-115	2	TRPM6
TETRAHYDROCANNABIVARIN	2	TRPV6
SOR-C13	1	TRPV6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRPM6	56	Binding:55, Functional:1
TRPM7	34	Binding:34
TRPV6	32	Binding:32

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

5 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)
TOFACITINIB	4	TRPM6
ECONAZOLE	4	TRPV6
TG100-115	2	TRPM6
TETRAHYDROCANNABIVARIN	2	TRPV6
SOR-C13	1	TRPV6

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TRPM6, TRPV6
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	TRPM7
E	Difficult family or no structure, no drug	0

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)
TRPM7	34	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases