Autosomal recessive nonsyndromic hearing loss 39

Summary

Autosomal recessive nonsyndromic hearing loss 39 (MONDO:0012003) is a disease caused by HGF (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: HGF (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 39
Mondo ID	MONDO:0012003
MeSH	C564265
OMIM	608265
DOID	DOID:0110497
NCIT	C129874
UMLS	C1842342
MedGen	374909
GARD	0022608
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 39 · autosomal recessive nonsyndromic deafness 39 · autosomal recessive nonsyndromic deafness caused by mutation in HGF · autosomal recessive nonsyndromic deafness type 39 · autosomal recessive nonsyndromic hearing loss 39 · deafness, autosomal recessive 39 · deafness, autosomal recessive type 39 · DFNB39 · HGF autosomal recessive nonsyndromic deafness

Data availability: 12 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › hearing loss, autosomal recessive › autosomal recessive nonsyndromic hearing loss 39

Related subtypes (101): autosomal recessive nonsyndromic hearing loss 5, autosomal recessive nonsyndromic hearing loss 1A, autosomal recessive nonsyndromic hearing loss 2, autosomal recessive nonsyndromic hearing loss 3, autosomal recessive nonsyndromic hearing loss 4, autosomal recessive nonsyndromic hearing loss 6, autosomal recessive nonsyndromic hearing loss 7, autosomal recessive nonsyndromic hearing loss 9, autosomal recessive nonsyndromic hearing loss 8, autosomal recessive nonsyndromic hearing loss 12, autosomal recessive nonsyndromic hearing loss 15, autosomal recessive nonsyndromic hearing loss 18A, autosomal recessive nonsyndromic hearing loss 17, autosomal recessive nonsyndromic hearing loss 13, autosomal recessive nonsyndromic hearing loss 21, autosomal recessive nonsyndromic hearing loss 14, autosomal recessive nonsyndromic hearing loss 16, autosomal recessive nonsyndromic hearing loss 20, autosomal recessive nonsyndromic hearing loss 26, autosomal recessive nonsyndromic hearing loss 27, autosomal recessive nonsyndromic hearing loss 22, autosomal recessive nonsyndromic hearing loss 31, autosomal recessive nonsyndromic hearing loss 30, autosomal recessive nonsyndromic hearing loss 33, autosomal recessive nonsyndromic hearing loss 37, autosomal recessive nonsyndromic hearing loss 38, autosomal recessive nonsyndromic hearing loss 40, autosomal recessive nonsyndromic hearing loss 35, autosomal recessive nonsyndromic hearing loss 32, autosomal recessive nonsyndromic hearing loss 36, autosomal recessive nonsyndromic hearing loss 48, autosomal recessive nonsyndromic hearing loss 23, autosomal recessive nonsyndromic hearing loss 42, autosomal recessive nonsyndromic hearing loss 46, autosomal recessive nonsyndromic hearing loss 53, autosomal recessive nonsyndromic hearing loss 28, autosomal recessive nonsyndromic hearing loss 51, autosomal recessive nonsyndromic hearing loss 47, autosomal recessive nonsyndromic hearing loss 55, autosomal recessive nonsyndromic hearing loss 62, autosomal recessive nonsyndromic hearing loss 49, autosomal recessive nonsyndromic hearing loss 44, autosomal recessive nonsyndromic hearing loss 66, autosomal recessive nonsyndromic hearing loss 59, autosomal recessive nonsyndromic hearing loss 65, autosomal recessive nonsyndromic hearing loss 67, autosomal recessive nonsyndromic hearing loss 68, autosomal recessive nonsyndromic hearing loss 24, autosomal recessive nonsyndromic hearing loss 63, autosomal recessive nonsyndromic hearing loss 45, autosomal recessive nonsyndromic hearing loss 1B, autosomal recessive nonsyndromic hearing loss 71, autosomal recessive nonsyndromic hearing loss 77, autosomal recessive nonsyndromic hearing loss 25, autosomal recessive nonsyndromic hearing loss 79, autosomal recessive nonsyndromic hearing loss 84A, autosomal recessive nonsyndromic hearing loss 85, autosomal recessive nonsyndromic hearing loss 91, autosomal recessive nonsyndromic hearing loss 83, autosomal recessive nonsyndromic hearing loss 74, autosomal recessive nonsyndromic hearing loss 61, autosomal recessive nonsyndromic hearing loss 89, autosomal recessive nonsyndromic hearing loss 29, autosomal recessive nonsyndromic hearing loss 96, autosomal recessive nonsyndromic hearing loss 86, autosomal recessive nonsyndromic hearing loss 98, autosomal recessive nonsyndromic hearing loss 93, autosomal recessive nonsyndromic hearing loss 70, autosomal recessive nonsyndromic hearing loss 84B, autosomal recessive nonsyndromic hearing loss 18B, autosomal recessive nonsyndromic hearing loss 88, autosomal recessive nonsyndromic hearing loss 76, autosomal recessive nonsyndromic hearing loss 101, autosomal recessive nonsyndromic hearing loss 102, autosomal recessive nonsyndromic hearing loss 103, autosomal recessive nonsyndromic hearing loss 104, autosomal recessive nonsyndromic hearing loss 97, hearing loss, autosomal recessive 111, hearing loss, autosomal recessive 118, with cochlear aplasia, hearing loss, autosomal recessive 119, hearing loss, autosomal recessive 117, hearing loss, autosomal recessive 112, hearing loss, autosomal recessive 113, hearing loss, autosomal recessive 100, hearing loss, autosomal recessive 94, hearing loss, autosomal recessive 114, hearing loss, autosomal recessive 115, hearing loss, autosomal recessive 99, hearing loss, autosomal recessive 106, hearing loss, autosomal recessive 107, hearing loss, autosomal recessive 108, hearing loss, autosomal recessive 57, hearing loss, autosomal recessive 109, hearing loss, autosomal recessive 116, hearing loss, autosomal recessive 110, hearing loss, autosomal recessive 120, hearing loss, autosomal recessive 121, hearing loss, autosomal recessive 122, hearing loss, autosomal recessive 123, autosomal recessive nonsyndromic hearing loss 124, hearing loss, autosomal recessive 125

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

12 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 2 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14949	NM_000601.6(HGF):c.495G>A (p.Ser165=)	HGF	Pathogenic	no assertion criteria provided
14950	NM_000601.6(HGF):c.482+1986_482+1988del	HGF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14951	NM_000601.6(HGF):c.482+1991_482+2000del	HGF	Pathogenic	no assertion criteria provided
178380	NM_000601.6(HGF):c.1891G>A (p.Val631Met)	HGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43606	NM_000601.6(HGF):c.1008G>A (p.Glu336=)	HGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1304450	NM_000601.6(HGF):c.6G>T (p.Trp2Cys)	HGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1392002	NM_000601.6(HGF):c.724C>T (p.Arg242Trp)	HGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
163660	NM_000601.6(HGF):c.983G>T (p.Arg328Leu)	HGF	Uncertain significance	criteria provided, single submitter
1802248	NM_000601.6(HGF):c.1810T>C (p.Cys604Arg)	HGF	Uncertain significance	criteria provided, single submitter
4078922	NM_000601.6(HGF):c.790G>A (p.Asp264Asn)	HGF	Uncertain significance	criteria provided, single submitter
1245186	NM_000601.6(HGF):c.866-22del	HGF	Benign	criteria provided, multiple submitters, no conflicts
43607	NM_000601.6(HGF):c.1272-4A>G	HGF	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
HGF	Strong	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 39	6
IL6	Strong	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 39	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HGF	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
IL6	Orphanet:85414	Systemic-onset juvenile idiopathic arthritis

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
HGF	HGNC:4893	ENSG00000019991	P14210	Hepatocyte growth factor	gencc,clinvar
IL6	HGNC:6018	ENSG00000136244	P05231	Interleukin-6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HGF	Hepatocyte growth factor	Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types.
IL6	Interleukin-6	Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism.

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HGF	Protease	yes		Kringle, Trypsin_dom, Peptidase_S1A
IL6	Other/Unknown	no		IL-6-like, 4_helix_cytokine-like_core, IL6/GCSF/MGF_CS

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
placenta	1
stromal cell of endometrium	1
visceral pleura	1
cartilage tissue	1
gall bladder	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HGF	221	broad	marker	placenta, stromal cell of endometrium, visceral pleura
IL6	200	ubiquitous	marker	cartilage tissue, vena cava, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL6	9,239
HGF	3,844

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HGF	P14210	36
IL6	P05231	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. 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
Interleukin-4 and Interleukin-13 signaling	2	102.9×	0.003	HGF, IL6
Drug-mediated inhibition of MET activation	1	2855.0×	0.004	HGF
MET activates STAT3	1	1903.3×	0.004	HGF
MET activates PTPN11	1	1142.0×	0.004	HGF
MET interacts with TNS proteins	1	1142.0×	0.004	HGF
MET Receptor Activation	1	951.7×	0.004	HGF
MET activates PI3K/AKT signaling	1	951.7×	0.004	HGF
MAPK1 (ERK2) activation	1	571.0×	0.004	IL6
MET receptor recycling	1	571.0×	0.004	HGF
CD163 mediating an anti-inflammatory response	1	571.0×	0.004	IL6
MAPK3 (ERK1) activation	1	519.1×	0.004	IL6
MET activates RAS signaling	1	519.1×	0.004	HGF
MET activates RAP1 and RAC1	1	519.1×	0.004	HGF
Interleukin-6 signaling	1	475.8×	0.004	IL6
Negative regulation of MET activity	1	259.6×	0.007	HGF
MET activates PTK2 signaling	1	190.3×	0.010	HGF
Interleukin-7 signaling	1	158.6×	0.011	HGF
Transcriptional Regulation by VENTX	1	132.8×	0.012	IL6
ADORA2B mediated anti-inflammatory cytokines production	1	126.9×	0.012	IL6
Interleukin-10 signaling	1	116.5×	0.012	IL6
Activation of STAT3 by cadherin engagement	1	81.6×	0.017	IL6
Constitutive Signaling by Aberrant PI3K in Cancer	1	63.4×	0.021	HGF
Post-translational protein phosphorylation	1	50.1×	0.024	IL6
Senescence-Associated Secretory Phenotype (SASP)	1	49.6×	0.024	IL6
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	48.4×	0.024	HGF
Platelet degranulation	1	43.9×	0.025	HGF
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.025	IL6
PIP3 activates AKT signaling	1	33.4×	0.031	HGF
RAF/MAP kinase cascade	1	30.5×	0.032	HGF

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
positive regulation of interleukin-10 production	2	401.2×	7e-04	HGF, IL6
positive regulation of osteoblast differentiation	2	224.7×	0.001	HGF, IL6
regulation of astrocyte activation	1	4213.0×	0.004	IL6
glucagon secretion	1	4213.0×	0.004	IL6
neutrophil apoptotic process	1	2808.7×	0.004	IL6
hepatic immune response	1	2808.7×	0.004	IL6
positive regulation of interleukin-21 production	1	2808.7×	0.004	IL6
regulation of vascular endothelial growth factor production	1	2106.5×	0.004	IL6
regulation of glucagon secretion	1	2106.5×	0.004	IL6
negative regulation of hydrogen peroxide-mediated programmed cell death	1	2106.5×	0.004	HGF
regulation of microglial cell activation	1	2106.5×	0.004	IL6
negative regulation of primary miRNA processing	1	2106.5×	0.004	IL6
skeletal muscle cell proliferation	1	1685.2×	0.004	HGF
regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling	1	1685.2×	0.004	HGF
positive regulation of apoptotic DNA fragmentation	1	1404.3×	0.004	IL6
vascular endothelial growth factor production	1	1203.7×	0.004	IL6
response to peptidoglycan	1	1203.7×	0.004	IL6
regulation of p38MAPK cascade	1	1203.7×	0.004	HGF
positive regulation of type B pancreatic cell apoptotic process	1	1203.7×	0.004	IL6
negative regulation of chemokine production	1	1053.2×	0.004	IL6
hepatocyte growth factor receptor signaling pathway	1	1053.2×	0.004	HGF
positive regulation of B cell activation	1	1053.2×	0.004	IL6
hepatocyte proliferation	1	1053.2×	0.004	IL6
inflammatory response to wounding	1	1053.2×	0.004	IL6
positive regulation of MAPK cascade	2	80.6×	0.004	HGF, IL6
negative regulation of apoptotic process	2	34.8×	0.004	HGF, IL6
germinal center B cell differentiation	1	842.6×	0.004	IL6
positive regulation of receptor signaling pathway via STAT	1	842.6×	0.004	IL6
negative regulation of interleukin-1-mediated signaling pathway	1	842.6×	0.004	IL6
negative regulation of lipid storage	1	766.0×	0.004	IL6

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
IL6	PREDNISOLONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL6	3	4
HGF	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PREDNISOLONE	4	IL6
FOSDAGROCORAT	2	IL6
BI 653048	1	IL6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
IL6	16	Binding:16
HGF	4	Binding:4

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

3 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)
PREDNISOLONE	4	IL6
FOSDAGROCORAT	2	IL6
BI 653048	1	IL6

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	IL6
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HGF
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)
HGF	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.