PDE1C

Chr 7AD

phosphodiesterase 1C

Also known as: DFNA74, Hcam3, cam-PDE 1C, hCam-3

NCBI Gene: 5137 ENSG00000154678 UniProt: Q14123 OMIM: 602987

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]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.701 OMIM phenotype

Clinical Summary— PDE1C

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Gene-Disease Validity (ClinGen)

autosomal dominant nonsyndromic hearing loss · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 194 VUS of 310 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.70LOEUF

pLI 0.000

Z-score 3.13

OE 0.49 (0.34–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.39Z-score

OE missense 0.81 (0.74–0.89)

355 obs / 436.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.34–0.70)

0≤0.351.4

Missense OE?0.81 (0.74–0.89)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 21 / 43.2Missense obs/exp: 355 / 436.6Syn Z: 0.28

This gene — mechanism propensity

0.80top 25%

GOF

0.72top 25%

LOF

0.2970th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

LOF1 literature citation · 60% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFAlthough neuronal migration disorder was not seen in our patient, this is the first patient described with haploinsufficiency of PDE1C possibly causing developmental delay.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 23664928 ↗

ClinVar Variant Classifications

310 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic5

VUS194

Likely Benign31

Benign57

Likely Pathogenic

194

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	3	2	0	0	5
VUS	2	191	1	0	194
Likely Benign	0	21	1	9	31
Benign	1	5	40	11	57
Total	6	219	42	20	287

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

23 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap PDE1C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →