Zimmermann-Laband syndrome 1

Summary

Zimmermann-Laband syndrome 1 (MONDO:0024526) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Zimmermann-Laband syndrome 1
Mondo ID	MONDO:0024526
OMIM	135500
UMLS	C4551773
MedGen	1639277
GARD	0015071
NORD	1344
Is cancer (heuristic)	no

Also known as: fibromatosis, gingival, with abnormal fingers, fingernails, Nose, and ears, and splenomegaly · KCNH1 Zimmermann-Laband syndrome · Laband Syndrome · Zimmermann-Laband syndrome 1 · Zimmermann-Laband syndrome caused by mutation in KCNH1 · ZLS1

Data availability: 35 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Zimmermann-Laband syndrome › Zimmermann-Laband syndrome 1

Related subtypes (2): Zimmermann-Laband syndrome 2, Zimmermann-Laband syndrome 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

35 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 8 pathogenic, 4 conflicting classifications of pathogenicity, 3 benign/likely benign, 3 benign, 2 likely pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
203434	NM_002238.3(KCNH1):c.[1066G>C;974C>A]		Pathogenic	no assertion criteria provided
183414	NM_001693.4(ATP6V1B2):c.1454G>C (p.Arg485Pro)	ATP6V1B2	Pathogenic	no assertion criteria provided
162520	NM_172362.3(KCNH1):c.1480A>G (p.Ile494Val)	KCNH1	Pathogenic	criteria provided, multiple submitters, no conflicts
183415	NM_172362.3(KCNH1):c.1123G>A (p.Gly375Arg)	KCNH1	Pathogenic	no assertion criteria provided
183416	NM_172362.3(KCNH1):c.1135C>G (p.Leu379Val)	KCNH1	Pathogenic	no assertion criteria provided
183417	NM_172362.3(KCNH1):c.1147G>C (p.Val383Leu)	KCNH1	Pathogenic	no assertion criteria provided
183418	NM_172362.3(KCNH1):c.1486G>A (p.Gly496Arg)	KCNH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183419	NM_172362.3(KCNH1):c.1055C>A (p.Ser352Tyr)	KCNH1	Pathogenic	no assertion criteria provided
2499611	NM_172362.3(KCNH1):c.1123G>C (p.Gly375Arg)	KCNH1	Pathogenic	criteria provided, single submitter
279981	NM_172362.3(KCNH1):c.1070G>A (p.Arg357Gln)	KCNH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1034355	NM_172362.3(KCNH1):c.1559G>A (p.Arg520Gln)	KCNH1	Likely pathogenic	criteria provided, single submitter
4530651	NM_172362.3(KCNH1):c.1070G>T (p.Arg357Leu)	KCNH1	Likely pathogenic	no assertion criteria provided
1216384	NM_172362.3(KCNH1):c.2482G>A (p.Gly828Arg)	KCNH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1418174	NM_172362.3(KCNH1):c.2392G>A (p.Val798Ile)	KCNH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1600068	NM_172362.3(KCNH1):c.2162T>C (p.Met721Thr)	KCNH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2894243	NM_172362.3(KCNH1):c.1115T>C (p.Ile372Thr)	KCNH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034356	NM_172362.3(KCNH1):c.2859_2861delinsTAC (p.Glu953_Ile954delinsAspThr)	KCNH1	Uncertain significance	criteria provided, single submitter
1306379	NM_172362.3(KCNH1):c.2788A>G (p.Arg930Gly)	KCNH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1307585	NM_172362.3(KCNH1):c.1022G>A (p.Arg341Lys)	KCNH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1339058	NM_172362.3(KCNH1):c.1180G>A (p.Ala394Thr)	KCNH1	Uncertain significance	criteria provided, single submitter
1426249	NM_172362.3(KCNH1):c.2930A>G (p.Gln977Arg)	KCNH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1706444	NM_172362.3(KCNH1):c.2658G>C (p.Lys886Asn)	KCNH1	Uncertain significance	criteria provided, single submitter
2627570	NM_172362.3(KCNH1):c.137A>G (p.Asn46Ser)	KCNH1	Uncertain significance	criteria provided, single submitter
3064695	NM_172362.3(KCNH1):c.115G>T (p.Asp39Tyr)	KCNH1	Uncertain significance	criteria provided, single submitter
3891442	NM_172362.3(KCNH1):c.2198C>T (p.Pro733Leu)	KCNH1	Uncertain significance	criteria provided, single submitter
587447	NM_172362.3(KCNH1):c.1034G>C (p.Gly345Ala)	KCNH1	Uncertain significance	criteria provided, single submitter
930362	NM_172362.3(KCNH1):c.1958C>T (p.Thr653Ile)	KCNH1	Uncertain significance	criteria provided, single submitter
930399	NM_172362.3(KCNH1):c.1717C>T (p.Arg573Cys)	KCNH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1174747	NM_172362.3(KCNH1):c.80-19dup	KCNH1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1206068	NM_172362.3(KCNH1):c.80-6del	KCNH1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
KCNH1	Moderate	Autosomal dominant	Zimmermann-Laband syndrome 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNH1	Orphanet:3473	Zimmermann-Laband syndrome
KCNH1	Orphanet:420561	Temple-Baraitser syndrome
ATP6V1B2	Orphanet:3473	Zimmermann-Laband syndrome
ATP6V1B2	Orphanet:79499	Autosomal dominant deafness-onychodystrophy syndrome
ATP6V1B2	Orphanet:79500	DOORS syndrome

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
KCNH1	HGNC:6250	ENSG00000143473	O95259	Voltage-gated delayed rectifier potassium channel KCNH1	gencc,clinvar
ATP6V1B2	HGNC:854	ENSG00000147416	P21281	V-type proton ATPase subunit B, brain isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNH1	Voltage-gated delayed rectifier potassium channel KCNH1	Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents which, on depolarization, reaches a steady-state level and do not inactivate.
ATP6V1B2	V-type proton ATPase subunit B, brain isoform	Non-catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNH1	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C
ATP6V1B2	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATPase_F1/V1/A1_a/bsu_N, ATPase_V1-cplx_bsu

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
Brodmann (1909) area 9	1
male germ line stem cell (sensu Vertebrata) in testis	1
prefrontal cortex	1
lateral nuclear group of thalamus	1
monocyte	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNH1	154	broad	marker	Brodmann (1909) area 9, prefrontal cortex, male germ line stem cell (sensu Vertebrata) in testis
ATP6V1B2	300	ubiquitous	marker	pons, monocyte, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP6V1B2	2,898
KCNH1	1,109

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP6V1B2	P21281	8
KCNH1	O95259	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	335.9×	0.013	ATP6V1B2
Insulin receptor recycling	1	190.3×	0.013	ATP6V1B2
Transferrin endocytosis and recycling	1	184.2×	0.013	ATP6V1B2
ROS and RNS production in phagocytes	1	167.9×	0.013	ATP6V1B2
Voltage gated Potassium channels	1	121.5×	0.015	KCNH1
Amino acids regulate mTORC1	1	100.2×	0.015	ATP6V1B2
Potassium Channels	1	67.2×	0.019	KCNH1
Ion channel transport	1	48.0×	0.023	ATP6V1B2
Neuronal System	1	22.1×	0.045	KCNH1

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
synaptic vesicle lumen acidification	1	468.1×	0.012	ATP6V1B2
vacuolar acidification	1	366.4×	0.012	ATP6V1B2
myoblast fusion	1	300.9×	0.012	KCNH1
ATP metabolic process	1	234.1×	0.012	ATP6V1B2
proton transmembrane transport	1	156.0×	0.012	ATP6V1B2
regulation of macroautophagy	1	147.8×	0.012	ATP6V1B2
regulation of membrane potential	1	115.4×	0.013	KCNH1
cellular response to calcium ion	1	100.3×	0.013	KCNH1
potassium ion transport	1	95.8×	0.013	KCNH1
potassium ion transmembrane transport	1	68.0×	0.016	KCNH1
regulation of cell population proliferation	1	57.7×	0.017	KCNH1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
ATP6V1B2	ENOXACIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP6V1B2	1	4
KCNH1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENOXACIN	4	ATP6V1B2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNH1	24	Binding:23, Toxicity:1
ATP6V1B2	3	Binding:3

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

1 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)
ENOXACIN	4	ATP6V1B2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATP6V1B2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	KCNH1
D	Druggable family + AlphaFold only, no drug	0
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)
KCNH1	24	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.