Hearing loss, autosomal dominant 74

Summary

Hearing loss, autosomal dominant 74 (MONDO:0029137) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hearing loss, autosomal dominant 74
Mondo ID	MONDO:0029137
OMIM	618140
DOID	DOID:0112165
UMLS	C4748334
MedGen	1648467
GARD	0018151
Is cancer (heuristic)	no

Also known as: deafness, autosomal dominant 74 · DFNA74

Data availability: 15 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant nonsyndromic hearing loss › hearing loss, autosomal dominant 74

Related subtypes (75): autosomal dominant nonsyndromic hearing loss 1, autosomal dominant nonsyndromic hearing loss 2A, autosomal dominant nonsyndromic hearing loss 4A, autosomal dominant nonsyndromic hearing loss 6, autosomal dominant nonsyndromic hearing loss 5, autosomal dominant nonsyndromic hearing loss 10, autosomal dominant nonsyndromic hearing loss 11, autosomal dominant nonsyndromic hearing loss 9, autosomal dominant nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 12, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss 17, autosomal dominant nonsyndromic hearing loss 16, autosomal dominant nonsyndromic hearing loss 20, autosomal dominant nonsyndromic hearing loss 23, autosomal dominant nonsyndromic hearing loss 25, autosomal dominant nonsyndromic hearing loss 18, autosomal dominant nonsyndromic hearing loss 24, autosomal dominant nonsyndromic hearing loss 22, autosomal dominant nonsyndromic hearing loss 30, autosomal dominant nonsyndromic hearing loss 36, autosomal dominant nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 44, autosomal dominant nonsyndromic hearing loss 48, autosomal dominant nonsyndromic hearing loss 41, autosomal dominant nonsyndromic hearing loss 49, autosomal dominant nonsyndromic hearing loss 43, autosomal dominant nonsyndromic hearing loss 28, autosomal dominant nonsyndromic hearing loss 31, autosomal dominant nonsyndromic hearing loss 47, autosomal dominant auditory neuropathy 1, autosomal dominant nonsyndromic hearing loss 53, autosomal dominant nonsyndromic hearing loss 27, autosomal dominant nonsyndromic hearing loss 59, autosomal dominant nonsyndromic hearing loss 3B, autosomal dominant nonsyndromic hearing loss 2B, autosomal dominant nonsyndromic hearing loss 50, autosomal dominant nonsyndromic hearing loss 51, autosomal dominant nonsyndromic hearing loss 64, autosomal dominant nonsyndromic hearing loss 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, autosomal dominant nonsyndromic hearing loss 65, autosomal dominant nonsyndromic hearing loss 67, autosomal dominant nonsyndromic hearing loss 40, autosomal dominant nonsyndromic hearing loss 69, autosomal dominant nonsyndromic hearing loss 68, autosomal dominant nonsyndromic hearing loss 70, autosomal dominant nonsyndromic hearing loss 66, hearing loss, autosomal dominant 77, hearing loss, autosomal dominant 81, hearing loss, autosomal dominant 82, hearing loss, autosomal dominant 83, hearing loss, autosomal dominant 84, hearing loss, autosomal dominant 80, hearing loss, autosomal dominant 37, hearing loss, autosomal dominant 75, hearing loss, autosomal dominant 76, hearing loss, autosomal dominant 71, hearing loss, autosomal dominant 72, hearing loss, autosomal dominant 73, hearing loss, autosomal dominant 34, with or without inflammation, hearing loss, autosomal dominant 78, hearing loss, autosomal dominant 79, hearing loss, autosomal dominant 85, hearing loss, autosomal dominant 86, hearing loss, autosomal dominant 87, hearing loss, autosomal dominant 88, hearing loss, autosomal dominant 89, hearing loss, autosomal dominant 90, autosomal dominant nonsyndromic hearing loss 91

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

15 retrieved; paginated sample, class counts are floors:

5 benign, 5 uncertain significance, 3 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
433528	NM_001191057.4(PDE1C):c.778G>T (p.Ala260Ser)	PDE1C	Pathogenic/Likely pathogenic	no assertion criteria provided
3250393	NM_001191057.4(PDE1C):c.1900C>T (p.Gln634Ter)	PDE1C	Likely pathogenic	criteria provided, single submitter
3250394	NM_001191057.4(PDE1C):c.2061C>A (p.Tyr687Ter)	PDE1C	Likely pathogenic	criteria provided, single submitter
4070944	NM_001191058.4(PDE1C):c.86-1G>A	PDE1C	Likely pathogenic	criteria provided, single submitter
2664004	NM_001191057.4(PDE1C):c.1071G>T (p.Gln357His)	PDE1C	Uncertain significance	no assertion criteria provided
2681474	NM_001191057.4(PDE1C):c.134G>A (p.Arg45Gln)	PDE1C	Uncertain significance	criteria provided, multiple submitters, no conflicts
3393401	NM_001191057.4(PDE1C):c.1083-7T>C	PDE1C	Uncertain significance	criteria provided, single submitter
3393402	NM_001191057.4(PDE1C):c.376C>G (p.Arg126Gly)	PDE1C	Uncertain significance	criteria provided, single submitter
3731506	NM_001322059.2(PDE1C):c.206A>T (p.His69Leu)	PDE1C	Uncertain significance	criteria provided, single submitter
1233118	NM_001191057.4(PDE1C):c.1773C>T (p.Asn591=)	PDE1C	Benign	criteria provided, multiple submitters, no conflicts
1234874	NM_001191057.4(PDE1C):c.1782C>T (p.Ala594=)	PDE1C	Benign	criteria provided, multiple submitters, no conflicts
1241492	NM_001191057.4(PDE1C):c.1830T>C (p.Gly610=)	PDE1C	Benign	criteria provided, multiple submitters, no conflicts
1251668	NM_001322059.2(PDE1C):c.471G>A (p.Glu157=)	PDE1C	Benign	criteria provided, multiple submitters, no conflicts
1294902	NM_001191057.4(PDE1C):c.1203+28A>G	PDE1C	Benign	criteria provided, multiple submitters, no conflicts
708869	NM_001191057.4(PDE1C):c.525C>T (p.Ser175=)	PDE1C	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
PDE1C	Supportive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDE1C	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

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
PDE1C	HGNC:8776	ENSG00000154678	Q14123	Dual specificity calcium/calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1C	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDE1C	Dual specificity calcium/calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1C	Calmodulin-dependent cyclic nucleotide phosphodiesterase with a dual specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDE1C	Transcription factor	no	3.1.4.17	PDEase_catalytic_dom, HD/PDEase_dom, PDE1_N

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
corpus callosum	1
endothelial cell	1
heart right ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDE1C	222	broad	marker	endothelial cell, heart right ventricle, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDE1C	883

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PDE1C	Q14123	71.53

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Cam-PDE 1 activation	1	2855.0×	4e-04	PDE1C

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
negative regulation of cAMP/PKA signal transduction	1	601.9×	0.003	PDE1C
signal transduction	1	16.1×	0.062	PDE1C

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
PDE1C	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE1C	15	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARDENAFIL	4	PDE1C
SILDENAFIL	4	PDE1C
VINPOCETINE	4	PDE1C
DIPYRIDAMOLE	4	PDE1C
NIMODIPINE	4	PDE1C
PAPAVERINE	3	PDE1C
NITRENDIPINE	3	PDE1C
BUFROLIN	2	PDE1C
OXAGRELATE	2	PDE1C
ZAPRINAST	2	PDE1C
CILOSTAMIDE	2	PDE1C
ETAZOLATE	2	PDE1C
IDOXIFENE	2	PDE1C
ROLIPRAM	2	PDE1C
EDELINONTRINE	2	PDE1C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PDE1C	185	Binding:175, ADMET:5, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDE1C	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PDE1C	185

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

15 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)
VARDENAFIL	4	PDE1C
SILDENAFIL	4	PDE1C
VINPOCETINE	4	PDE1C
DIPYRIDAMOLE	4	PDE1C
NIMODIPINE	4	PDE1C
PAPAVERINE	3	PDE1C
NITRENDIPINE	3	PDE1C
BUFROLIN	2	PDE1C
OXAGRELATE	2	PDE1C
ZAPRINAST	2	PDE1C
CILOSTAMIDE	2	PDE1C
ETAZOLATE	2	PDE1C
IDOXIFENE	2	PDE1C
ROLIPRAM	2	PDE1C
EDELINONTRINE	2	PDE1C

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PDE1C
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.