Renal hypomagnesemia 5 with ocular involvement

Summary

Renal hypomagnesemia 5 with ocular involvement (MONDO:0009548) is a disease caused by CLDN19 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal gene: CLDN19 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 126
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		72	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0000112	Nephropathy	Very frequent (80-99%)
HP:0000545	Myopia	Very frequent (80-99%)
HP:0000567	Chorioretinal coloboma	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0000787	Nephrolithiasis	Very frequent (80-99%)
HP:0001116	Macular coloboma	Very frequent (80-99%)
HP:0007703	Abnormality of retinal pigmentation	Very frequent (80-99%)
HP:0100530	Abnormality of calcium-phosphate metabolism	Very frequent (80-99%)
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000790	Hematuria	Frequent (30-79%)
HP:0001537	Umbilical hernia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	renal hypomagnesemia 5 with ocular involvement
Mondo ID	MONDO:0009548
MeSH	C536148
OMIM	248190
Orphanet	2196
DOID	DOID:0060881
UMLS	C4721891
MedGen	1648449
GARD	0003451
Is cancer (heuristic)	no

Also known as: FHHNC with severe ocular involvement · FHHNCOI · HOMG5 · hypercalciuria-bilateral macular coloboma syndrome · hypomagnesemia 5, renal, with ocular involvement · idiopathic hypercalciuria with bilateral macular colobomata · Meier Blumberg Imahorn syndrome · Meier-Blumberg-Imahorn syndrome

Data availability: 126 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 hypercalciuria and nephrocalcinosis › renal hypomagnesemia 5 with ocular involvement

Related subtypes (1): renal hypomagnesemia 3

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

126 retrieved; paginated sample, class counts are floors:

79 uncertain significance, 14 likely pathogenic, 11 benign, 7 pathogenic, 6 conflicting classifications of pathogenicity, 4 likely benign, 3 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333609	NM_148960.3(CLDN19):c.427del (p.Leu143fs)	CLDN19	Pathogenic	criteria provided, multiple submitters, no conflicts
1361	NM_148960.3(CLDN19):c.59G>A (p.Gly20Asp)	CLDN19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1362	NM_148960.3(CLDN19):c.169C>G (p.Gln57Glu)	CLDN19	Pathogenic	no assertion criteria provided
1363	NM_148960.3(CLDN19):c.269T>C (p.Leu90Pro)	CLDN19	Pathogenic	no assertion criteria provided
1687613	NM_148960.3(CLDN19):c.474-1G>C	CLDN19	Pathogenic	criteria provided, single submitter
2202737	NM_148960.3(CLDN19):c.223G>A (p.Gly75Ser)	CLDN19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501010	NM_148960.3(CLDN19):c.181C>T (p.Gln61Ter)	CLDN19	Pathogenic	no assertion criteria provided
548636	NM_148960.3(CLDN19):c.269T>G (p.Leu90Arg)	CLDN19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
548637	NM_148960.3(CLDN19):c.169C>T (p.Gln57Ter)	CLDN19	Pathogenic	no assertion criteria provided
560599	NM_148960.3(CLDN19):c.388G>T (p.Gly130Cys)	CLDN19	Pathogenic	no assertion criteria provided
930213	NM_006580.4(CLDN16):c.67G>A (p.Ala23Thr)	CLDN16	Likely pathogenic	no assertion criteria provided
1333489	NM_148960.3(CLDN19):c.83C>T (p.Pro28Leu)	CLDN19	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068324	NM_148960.3(CLDN19):c.162C>A (p.Cys54Ter)	CLDN19	Likely pathogenic	criteria provided, single submitter
3242162	NM_148960.3(CLDN19):c.535G>C (p.Gly179Arg)	CLDN19	Likely pathogenic	criteria provided, single submitter
3384045	NM_148960.3(CLDN19):c.263T>A (p.Val88Glu)	CLDN19	Likely pathogenic	criteria provided, single submitter
3384048	NM_148960.3(CLDN19):c.241C>T (p.Arg81Trp)	CLDN19	Likely pathogenic	criteria provided, single submitter
3583940	NM_148960.3(CLDN19):c.263_270dup (p.Gly91fs)	CLDN19	Likely pathogenic	criteria provided, single submitter
3583944	NM_148960.3(CLDN19):c.223+1G>A	CLDN19	Likely pathogenic	criteria provided, single submitter
3583947	NM_148960.3(CLDN19):c.178_182delinsCCC (p.Gly60fs)	CLDN19	Likely pathogenic	criteria provided, single submitter
3583982	NM_148960.3(CLDN19):c.140_141del (p.Leu46_Tyr47insTer)	CLDN19	Likely pathogenic	criteria provided, single submitter
3777110	NM_148960.3(CLDN19):c.223G>C (p.Gly75Arg)	CLDN19	Likely pathogenic	criteria provided, single submitter
4074278	NM_148960.3(CLDN19):c.392T>G (p.Leu131Arg)	CLDN19	Likely pathogenic	criteria provided, single submitter
4294299	NM_148960.3(CLDN19):c.220del (p.Asp74fs)	CLDN19	Likely pathogenic	criteria provided, single submitter
974422	NM_148960.3(CLDN19):c.530T>G (p.Leu177Arg)	CLDN19	Likely pathogenic	criteria provided, single submitter
1053033	NM_148960.3(CLDN19):c.229A>G (p.Ile77Val)	CLDN19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2186248	NM_148960.3(CLDN19):c.429G>T (p.Leu143=)	CLDN19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3583886	NM_148960.3(CLDN19):c.626+7C>A	CLDN19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
548672	NM_148960.3(CLDN19):c.535G>A (p.Gly179Ser)	CLDN19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875466	NM_148960.3(CLDN19):c.498C>T (p.Phe166=)	CLDN19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
954207	NM_148960.3(CLDN19):c.526G>A (p.Val176Met)	CLDN19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CLDN19	Definitive	Autosomal recessive	renal hypomagnesemia 5 with ocular involvement	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLDN19	Orphanet:2196	Primary hypomagnesemia with hypercalciuria and nephrocalcinosis with severe ocular involvement
CLDN16	Orphanet:31043	Primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement

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
CLDN19	HGNC:2040	ENSG00000164007	Q8N6F1	Claudin-19	gencc,clinvar
CLDN16	HGNC:2037	ENSG00000113946	Q9Y5I7	Claudin-16	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLDN19	Claudin-19	Forms paracellular channels: coassembles with CLDN16 into tight junction strands with cation-selective channels through the strands, conveying epithelial permeability in a process known as paracellular tight junction permeability.
CLDN16	Claudin-16	Forms paracellular channels: coassembles with CLDN19 into tight junction strands with cation-selective channels through the strands, conveying epithelial permeability in a process known as paracellular tight junction permeability.

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)
CLDN19	Other/Unknown	no		PMP22/EMP/MP20/Claudin, Claudin, Claudin_CS
CLDN16	Other/Unknown	no		Claudin16, PMP22/EMP/MP20/Claudin, Claudin

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
dorsal root ganglion	1
pigmented layer of retina	1
trigeminal ganglion	1
adult mammalian kidney	1
male germ line stem cell (sensu Vertebrata) in testis	1
olfactory segment of nasal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLDN19	143	broad	marker	trigeminal ganglion, dorsal root ganglion, pigmented layer of retina
CLDN16	127	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, olfactory segment of nasal mucosa, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLDN19	979
CLDN16	637

Intra-cohort edges

A	B	Sources
CLDN16	CLDN19	intact, string_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLDN19	Q8N6F1	81.08
CLDN16	Q9Y5I7	76.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Tight junction interactions	2	368.4×	7e-06	CLDN19, CLDN16

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
paracellular transport	2	2407.4×	3e-06	CLDN19, CLDN16
renal absorption	2	1685.2×	3e-06	CLDN19, CLDN16
calcium-independent cell-cell adhesion	2	802.5×	9e-06	CLDN19, CLDN16
bicellular tight junction assembly	2	330.4×	4e-05	CLDN19, CLDN16
intercellular transport	1	8426.0×	4e-04	CLDN16
regulation of transepithelial transport	1	2106.5×	0.001	CLDN19
cell adhesion	2	37.5×	0.002	CLDN19, CLDN16
metal ion transport	1	936.2×	0.002	CLDN16
retinal pigment epithelium development	1	842.6×	0.002	CLDN19
cell junction assembly	1	842.6×	0.002	CLDN19
neuronal action potential propagation	1	702.2×	0.002	CLDN19
intracellular monoatomic cation homeostasis	1	561.7×	0.003	CLDN16
negative regulation of cell migration	1	55.8×	0.025	CLDN19
visual perception	1	39.8×	0.030	CLDN19
actin cytoskeleton organization	1	39.6×	0.030	CLDN19
negative regulation of gene expression	1	34.5×	0.032	CLDN19
negative regulation of cell population proliferation	1	21.1×	0.050	CLDN19
positive regulation of gene expression	1	19.4×	0.051	CLDN19

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
CLDN19	0	0
CLDN16	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	CLDN19, CLDN16

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)
CLDN19	0	—
CLDN16	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.