PDE1C

protein-coding

phosphodiesterase 1C, the group of Phosphodiesterases

Gene summary

This gene encodes an enzyme that belongs to the 3'5'-cyclic nucleotide phosphodiesterase family. Members of this family catalyze hydrolysis of the cyclic nucleotides, cyclic adenosine monophosphate and cyclic guanosine monophosphate, to the corresponding nucleoside 5'-monophosphates. The enzyme encoded by this gene regulates proliferation and migration of vascular smooth muscle cells, and neointimal hyperplasia. This enzyme also plays a role in pathological vascular remodeling by regulating the stability of growth factor receptors, such as PDGF-receptor-beta. [provided by RefSeq, Jul 2016]

MANE transcript

NM_001191057.4

Inheritance

ClinVar variants

P:4U:99B:45

Top phenotype

Deafness, autosomal dominant 74

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr7:31,751,179-32,428,131

External References & Databases

Ensembl (ENSG00000154678)

Transcript & Mutation Effects

hg38 • Region Span ~677.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

hearing loss, autosomal dominant 74LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0029137

Submitter: Ambry Genetics

autosomal dominant nonsyndromic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: ClinGen

PDE1C was first reported in relation to autosomal dominant nonsyndromic hearing loss (DFNA74) in 2018 (Wang et al. 2018, PMID: 29860631). This gene encodes phosphodiesterase 1C, a member of the cyclic nucleotide phosphodiesterase 1 family (PMID: 1326532). Four missense variants have been reported in association with hearing loss; however, two of the individuals reported had additional variants in hearing loss-associated genes and were not included in the scoring of this gene-disease validity scoring (PMID: 38400873, 34556655). One large family with autosomal dominant, postlingual, and progressive hearing loss was reported to have a missense variant in PDE1C identified via whole exome sequencing and segregated with disease (PMID: 29860631). Of note, this variant was also found to be present in gnomAD at a frequency of 0.022% (14/44830) in East Asian chromosomes. An in vitro phosphodiesterase functional assay was performed and the mutant was found to affect both cAMP and cGMP hydrolysis (PMID: 29860631). A second missense variant was identified in a cohort of individuals with hearing loss, though specific phenotypic information was not reported (PMID: 36597107). PDE1C is expressed in outer (OHC) and inner (IHC) hair cells in mouse cochlea (PMID: 29860631). It is also expressed in the human inner ear, with the highest expression in glial and chondrocytes (https://umgear.org/). In summary, there is limited evidence supporting this gene disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Gene Curation Expert Panel on April 15, 2026. Gene Clinical Validity Standard Operating Procedures (SOP) version 12.

hearing loss, autosomal dominant 74LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0029137

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 74AD

Manifestation: Audiologic/Otolaryngologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 29860631

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDE1C variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 108

PDE1C-related disorderTotal: 46

not providedTotal: 23

Hearing loss, autosomal dominant 74Total: 12

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Prostate cancerTotal: 1

Autosomal dominant nonsyndromic hearing lossTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001191057.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	22 clinvar	1 clinvar	25
missense		2 clinvar	91 clinvar	19 clinvar	3 clinvar	115
nonsense		2 clinvar	1 clinvar			3
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	4	99	41	4	148

Highest pathogenic variant AF is 0.000047750516

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001191057.4	RefSeq	NP_001177986.1	18	MANE Select
ENST00000396191.6	Ensembl	ENSP00000379494.1	18	MANE Select
NM_001191056.3	RefSeq	NP_001177985.1	17	Standard
NM_001191058.4	RefSeq	NP_001177987.2	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Calcium signaling pathway - Homo sapiens (human)
Renin secretion - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Taste transduction - Homo sapiens (human)
Olfactory transduction - Homo sapiens (human)

Biological Process

signal transduction

Molecular Function

calmodulin-dependent cyclic-nucleotide phosphodiesterase activity
calmodulin binding
metal ion binding
calcium- and calmodulin-regulated 3',5'-cyclic-GMP phosphodiesterase activity

Cellular Component

cytosol
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396193
Coding exons: 19
Length: 548149
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.39	355	437	0.813	0.0000247	5035
Missense (PolyPhen)		112	173.94	0.64389		2037
Synonymous	0.282	155	160	0.972	0.00000913	1423
Loss of Function	3.13	21	43.2	0.486	0.00000229	507

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a high affinity for both cAMP and cGMP.;

Recessive Scores

pRec: 0.174

Intolerance Scores

LoFtool: 0.750
RVIS EVS: 0.05
RVIS percentile EVS: 57.52

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.617

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium