DNM1

Chr 9ADAR

dynamin 1

Also known as: DEE31, DEE31A, DEE31B, DNM, EIEE31

NCBI Gene: 1759 ENSG00000106976 UniProt: Q05193 OMIM: 602377

The protein tubulates and severs membranes through its mechanochemical GTPase activity and is essential for clathrin-mediated endocytosis and vesicular trafficking processes. Mutations cause developmental and epileptic encephalopathy 31A (autosomal dominant) and 31B (autosomal recessive), with the gene being highly intolerant to loss-of-function variants. Disease can result from different mechanisms depending on the specific variant, with some mutations likely causing haploinsufficiency while others may act through dominant-negative or gain-of-function effects.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the dynamin subfamily of GTP-binding proteins. The encoded protein possesses unique mechanochemical properties used to tubulate and sever membranes, and is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Actin and other cytoskeletal proteins act as binding partners for the encoded protein, which can also self-assemble leading to stimulation of GTPase activity. More than sixty highly conserved copies of the 3' region of this gene are found elsewhere in the genome, particularly on chromosomes Y and 15. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.252 OMIM phenotypes

Clinical Summary— DNM1

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

69 unique Pathogenic / Likely Pathogenic· 387 VUS of 1052 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DNM1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.25LOEUF

pLI 0.999

Z-score 5.54

OE 0.13 (0.07–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

5.18Z-score

OE missense 0.35 (0.31–0.40)

181 obs / 510.2 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.25)

0≤0.351.4

Missense OE?0.35 (0.31–0.40)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 6 / 47.0Missense obs/exp: 181 / 510.2Syn Z: 1.67

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateDNM1-related microcephaly, developmental and epileptic encephalopathy (biallelic)LOFAR

strongDNM1-related microcephaly, developmental and epileptic encephalopathy (monoallelic)DNAD

This gene — mechanism propensity

0.5674th %ile

GOF

0.4875th %ile

LOF

0.62top 25%

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

LOF25% of P/LP variants are LoF · LOEUF 0.25

DN1 literature citation

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

DNAll mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.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 28667181 ↗

ClinVar Variant Classifications

1052 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30

Likely Pathogenic39

VUS387

Likely Benign459

Benign76

Conflicting46

Pathogenic

Likely Pathogenic

387

VUS

459

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	18	1	0	30
Likely Pathogenic	6	32	1	0	39
VUS	16	312	44	15	387
Likely Benign	2	23	203	231	459
Benign	0	15	52	9	76
Conflicting	—				46
Total	35	400	301	255	1,037

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap DNM1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →