DES

Chr 2ADAR

desmin

Also known as: CDCD3, CSM1, CSM2, LGMD1D, LGMD1E, LGMD2R

NCBI Gene: 1674 ENSG00000175084 UniProt: P17661 OMIM: 125660

Desmin encodes a muscle-specific intermediate filament protein that forms filamentous networks connecting myofibrils to each other and to the plasma membrane in cardiac and skeletal muscle. Mutations cause desmin-related myopathy and myofibrillar myopathy type 1, presenting as familial cardiac and skeletal myopathy, dilated cardiomyopathy, distal myopathies, or scapuloperoneal syndrome through dominant-negative mechanisms. Inheritance is autosomal dominant or autosomal recessive.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a muscle-specific class III intermediate filament. Homopolymers of this protein form a stable intracytoplasmic filamentous network connecting myofibrils to each other and to the plasma membrane. Mutations in this gene are associated with desmin-related myopathy, a familial cardiac and skeletal myopathy (CSM), and with distal myopathies. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.603 OMIM phenotypes

Clinical Summary— DES

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Gene-Disease Validity (ClinGen)

arrhythmogenic right ventricular cardiomyopathy · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

127 unique Pathogenic / Likely Pathogenic· 685 VUS of 1337 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DES

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.009

Z-score 3.05

OE 0.33 (0.19–0.60)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.77Z-score

OE missense 0.71 (0.63–0.79)

206 obs / 291.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.19–0.60)

0≤0.351.4

Missense OE?0.71 (0.63–0.79)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 8 / 24.2Missense obs/exp: 206 / 291.1Syn Z: 1.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDES-related myofibrillar myopathyOTHERAR

definitiveDES-related myofibrillar myopathyOTHERAD

definitiveDES-related dilated cardiomyopathyOTHERAD

This gene — mechanism propensity

0.96top 5%

GOF

0.87top 5%

LOF

0.1598th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-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 · 1 literature citation

GOFprediction above median

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

DNWe conclude that the L345P desmin missense mutation causes myopathy by interfering in a dominant-negative manner with the dimerization-polymerization process of intermediate filament assembly.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 10545598 ↗

ClinVar Variant Classifications

1337 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61

Likely Pathogenic66

VUS685

Likely Benign384

Benign27

Conflicting98

Pathogenic

Likely Pathogenic

685

VUS

384

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	37	19	5	0	61
Likely Pathogenic	29	36	1	0	66
VUS	25	606	43	11	685
Likely Benign	1	3	129	251	384
Benign	0	0	22	5	27
Conflicting	—				98
Total	92	664	200	267	1,321

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap DES — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

DES · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — DES

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Cystic Fibrosis

Microbial Biomarkers of EArly Pseudomonas Aeruginosa Colonization in CHildren With Cystic Fibrosis

ACTIVE NOT RECRUITING

NCT03947957Phase NAUniversity Hospital, BrestStarted 2020-10-02

collection of expectoration, stools and blood

Colon AdenocarcinomaMicrosatellite Stable Colon CarcinomaStage IIB Colon Cancer AJCC v8

Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer

ACTIVE NOT RECRUITING

NCT05710406Phase PHASE2, PHASE3Alliance for Clinical Trials in OncologyStarted 2023-08-16

EncorafenibCetuximabBiospecimen Collection

Aggressive Fibromatosis

National Clinical-biological Prospective Cohort of Incident Cases of Aggressive Fibromatosis (ALTITUDES)

ACTIVE NOT RECRUITING

NCT02867033Phase NACentre Oscar LambretStarted 2016-03-22

biopsybiobank constitutionColoscopy

KRAS Gene MutationRecurrent Lung Non-Small Cell CarcinomaStage IV Lung Non-Small Cell Cancer AJCC v7

Trametinib and Docetaxel in Treating Patients With Recurrent or Stage IV KRAS Mutation Positive Non-small Cell Lung Cancer

ACTIVE NOT RECRUITING

NCT02642042Phase PHASE2National Cancer Institute (NCI)Started 2016-07-18

DocetaxelLaboratory Biomarker AnalysisTrametinib

Prostate Cancer

Comparative Study of Radiotherapy Treatments to Treat High Risk Prostate Cancer Patients

ACTIVE NOT RECRUITING

NCT02303327Phase PHASE3Sir Mortimer B. Davis - Jewish General HospitalStarted 2015-01

EBRT + HDR brachytherapy boostHypofractionated Dose Escalation RadiotherapyAndrogen deprivation therapy

Anatomic Stage I Breast Cancer AJCC v8Anatomic Stage II Breast Cancer AJCC v8Anatomic Stage III Breast Cancer AJCC v8

Additional Support Program Via Text Messaging and Telephone-Based Counseling for Breast Cancer Patients Receiving Hormonal Therapy

ACTIVE NOT RECRUITING

NCT04379570Phase PHASE3Alliance for Clinical Trials in OncologyStarted 2021-02-15

Educational InterventionText Message-based Navigation InterventionMotivational Interviewing

Spinal Muscular Atrophy

Outcome Measures and Biomarkers in a Cohort of Spinal Muscular Atrophy Type III/ IV Patients

ACTIVE NOT RECRUITING

NCT04690998Phase NAAssistance Publique Hopitaux De MarseilleStarted 2021-07-13

Blood SamplesMRI

Metastatic Pancreatic AdenocarcinomaStage IV Pancreatic Cancer AJCC v8

Testing the Addition of Pembrolizumab, an Immunotherapy Cancer Drug to Olaparib Alone as Therapy for Patients With Pancreatic Cancer That Has Spread With Inherited BRCA Mutations

ACTIVE NOT RECRUITING

NCT04548752Phase PHASE2National Cancer Institute (NCI)Started 2021-02-22

Biopsy ProcedureBiospecimen CollectionComputed Tomography

Previously Treated Non-Small Cell Lung Cancer

Lung-MAP: A Master Screening Protocol for Previously-Treated Non-Small Cell Lung Cancer

RECRUITING

NCT03851445Phase PHASE2, PHASE3SWOG Cancer Research NetworkStarted 2019-02-06

Screening Platform

Endometrial AdenocarcinomaEndometrial Mixed Cell AdenocarcinomaEndometrial Serous Adenocarcinoma

Testing the Combination of Olaparib and Durvalumab, Cediranib and Durvalumab, Olaparib and Capivasertib, and Cediranib Alone in Recurrent or Refractory Endometrial Cancer Following the Earlier Phase of the Study That Tested Olaparib and Cediranib in Comparison to Cediranib Alone, and Olaparib Alone

ACTIVE NOT RECRUITING

NCT03660826Phase PHASE2National Cancer Institute (NCI)Started 2018-09-27

Biospecimen CollectionBone Marrow AspirateBone Marrow Biopsy

Infiltrating Bladder Urothelial CarcinomaStage II Bladder Urothelial CarcinomaStage III Bladder Urothelial Carcinoma

Gemcitabine and Cisplatin Without Cystectomy for Patients With Muscle Invasive Bladder Urothelial Cancer and Select Genetic Alterations

ACTIVE NOT RECRUITING

NCT03609216Phase PHASE2Alliance for Clinical Trials in OncologyStarted 2018-12-10

Gemcitabine HydrochlorideCisplatinPegfilgrastim

Breast Screening

Digital Tomosynthesis Mammography and Digital Mammography in Screening Patients for Breast Cancer

ACTIVE NOT RECRUITING

NCT03233191Phase PHASE3ECOG-ACRIN Cancer Research GroupStarted 2017-09-28