DES

desmin, the group of Intermediate filaments Type III

Basic information

Region (hg38): 2:219418377-219426735

Links

ENSG00000175084 ∙ NCBI:1674 ∙ OMIM:125660 ∙ HGNC:2770 ∙ Uniprot:P17661 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• atrioventricular block (Strong), mode of inheritance: AD
• atrioventricular block (Strong), mode of inheritance: AR
• myofibrillar myopathy 1 (Definitive), mode of inheritance: Semidominant
• dilated cardiomyopathy 1I (Strong), mode of inheritance: AD
• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• neurogenic scapuloperoneal syndrome, Kaeser type (Supportive), mode of inheritance: AD
• dilated cardiomyopathy 1I (Definitive), mode of inheritance: AD
• myofibrillar myopathy 1 (Definitive), mode of inheritance: AD
• myofibrillar myopathy 1 (Definitive), mode of inheritance: AR
• dilated cardiomyopathy 1I (Strong), mode of inheritance: AD
• myofibrillar myopathy 1 (Strong), mode of inheritance: AD
• myofibrillar myopathy 1 (Strong), mode of inheritance: AR
• dilated cardiomyopathy (Definitive), mode of inheritance: AD
• arrhythmogenic right ventricular cardiomyopathy (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myopathy, myofibrillar 1; Cardiomyopathy, dilated, 1I	AD/AR	Cardiovascular	In myofibrillar myopathy, individuals typically present with slowly progressive weakness, and a significant proportion of individuals demonstrate cardiomyopathy, such that surveillance for arrhythmia or conduction defects may allow early treatment (eg, pacemaker, ICD); Cardiac transplantation may be necessary in individuals with severe forms of cardiomyopathy; In dilated cardiomyopathy, surveillance (eg, with electrocardiogram and echocardiogram) can allow early detection and interventions (including medications) in order to ameliorate morbidity and mortality	Cardiovascular; Musculoskeletal; Neurologic	5828910; 8114783; 7672786; 9697706; 9736733; 10430757; 10545598; 11073539; 17221859; 17439987; 19433360; 19879535; 20301672; 20664348; 20718792; 22215463; 23687351; 24200904; 31024060

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DES gene.

• Desmin-related myofibrillar myopathy (39 variants)
• not provided (15 variants)
• Dilated cardiomyopathy 1I;Desmin-related myofibrillar myopathy;Neurogenic scapuloperoneal syndrome, Kaeser type (2 variants)
• Primary dilated cardiomyopathy;Desmin-related myofibrillar myopathy (1 variants)
• Neurogenic scapuloperoneal syndrome, Kaeser type (1 variants)
• Dilated cardiomyopathy 1I (1 variants)
• Primary dilated cardiomyopathy (1 variants)
• Myofibrillar myopathy (1 variants)
• Cardiovascular phenotype (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DES gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			10	189	5	204
missense	10	22	469	2		503
nonsense	12	7	2			21
start loss		2				2
frameshift	14	5	7			26
inframe indel	2	2	20			24
splice donor/acceptor (+/-2bp)	1	9	5			15
splice region	1		21	17		39
non coding	1		13	79	16	109
Total	40	47	526	270	21

Highest pathogenic variant AF is 0.0000329

Variants in DES

This is a list of pathogenic ClinVar variants found in the DES region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-219418389-C-T		Neurogenic scapuloperoneal syndrome, Kaeser type • Dilated cardiomyopathy 1I • Myofibrillar Myopathy, Dominant • Desmin-related myofibrillar myopathy	Uncertain significance (Jan 12, 2018)
2-219418409-C-T		Dilated cardiomyopathy 1I • Neurogenic scapuloperoneal syndrome, Kaeser type • Desmin-related myofibrillar myopathy	Uncertain significance (Jan 13, 2018)
2-219418416-C-T		not specified	Likely benign (Mar 08, 2018)
2-219418419-G-A		not specified • Myofibrillar Myopathy, Dominant • Dilated cardiomyopathy 1I • Neurogenic scapuloperoneal syndrome, Kaeser type • Desmin-related myofibrillar myopathy	Benign/Likely benign (Apr 27, 2017)
2-219418432-T-A			Likely benign (Apr 03, 2018)
2-219418432-T-TGCGCCCGCCAGCC		not specified	Benign (Oct 19, 2020)
2-219418446-T-TGCGCCCGCCAGCC			Benign (Mar 03, 2015)
2-219418454-G-A		not specified	Uncertain significance (Feb 11, 2022)
2-219418456-C-G		not specified • Dilated cardiomyopathy 1I	Conflicting classifications of pathogenicity (Jul 25, 2019)
2-219418457-G-A		Dilated cardiomyopathy 1I • Neurogenic scapuloperoneal syndrome, Kaeser type • Myofibrillar Myopathy, Dominant • not specified • Desmin-related myofibrillar myopathy	Uncertain significance (Feb 01, 2021)
2-219418461-C-T		Cardiomyopathy	Uncertain significance (-)
2-219418463-A-G		Desmin-related myofibrillar myopathy • Cardiovascular phenotype	Conflicting classifications of pathogenicity (May 17, 2024)
2-219418464-T-C		Desmin-related myofibrillar myopathy	Likely pathogenic (Jun 29, 2020)
2-219418467-G-T		Desmin-related myofibrillar myopathy	Pathogenic/Likely pathogenic (Feb 08, 2023)
2-219418469-C-G		DES-related disorder	Uncertain significance (Dec 29, 2023)
2-219418469-C-T		Desmin-related myofibrillar myopathy	Pathogenic/Likely pathogenic (May 04, 2023)
2-219418470-A-G		Desmin-related myofibrillar myopathy	Uncertain significance (Oct 03, 2022)
2-219418471-G-A		Cardiovascular phenotype • Desmin-related myofibrillar myopathy	Likely benign (Dec 01, 2023)
2-219418472-G-A		Desmin-related myofibrillar myopathy	Uncertain significance (Dec 21, 2020)
2-219418473-C-A		Desmin-related myofibrillar myopathy	Uncertain significance (Mar 12, 2022)
2-219418474-C-A		Desmin-related myofibrillar myopathy • Cardiovascular phenotype	Likely benign (Dec 17, 2023)
2-219418474-C-G		Desmin-related myofibrillar myopathy	Likely benign (Feb 03, 2020)
2-219418477-C-A		Cardiovascular phenotype	Uncertain significance (Jan 23, 2023)
2-219418479-C-G		Desmin-related myofibrillar myopathy • Cardiovascular phenotype	Uncertain significance (Oct 12, 2021)
2-219418479-C-T		Desmin-related myofibrillar myopathy	Uncertain significance (Jan 09, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DES	protein_coding	protein_coding	ENST00000373960	9	8363

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00883	0.991	125726	0	22	125748	0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.77	206	291	0.708	0.0000191	2986
Missense in Polyphen		79	106.97	0.73855		1097
Synonymous	1.11	108	124	0.873	0.00000789	923
Loss of Function	3.05	8	24.2	0.331	0.00000141	249

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000123	0.000123
Ashkenazi Jewish	0.000827	0.000794
East Asian	0.000116	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000703	0.0000703
Middle Eastern	0.000116	0.000109
South Asian	0.0000327	0.0000327
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Muscle-specific type III intermediate filament essential for proper muscular structure and function. Plays a crucial role in maintaining the structure of sarcomeres, inter-connecting the Z-disks and forming the myofibrils, linking them not only to the sarcolemmal cytoskeleton, but also to the nucleus and mitochondria, thus providing strength for the muscle fiber during activity (PubMed:25358400). In adult striated muscle they form a fibrous network connecting myofibrils to each other and to the plasma membrane from the periphery of the Z-line structures (PubMed:24200904, PubMed:25394388, PubMed:26724190). May act as a sarcomeric microtubule-anchoring protein: specifically associates with detyrosinated tubulin-alpha chains, leading to buckled microtubules and mechanical resistance to contraction. Contributes to the transcriptional regulation of the NKX2-5 gene in cardiac progenitor cells during a short period of cardiomyogenesis and in cardiac side population stem cells in the adult. Plays a role in maintaining an optimal conformation of nebulette (NEB) on heart muscle sarcomeres to bind and recruit cardiac alpha-actin (By similarity). {ECO:0000250|UniProtKB:P31001, ECO:0000269|PubMed:24200904, ECO:0000269|PubMed:25394388, ECO:0000269|PubMed:26724190, ECO:0000303|PubMed:25358400}.
• Disease: DISEASE: Myopathy, myofibrillar, 1 (MFM1) [MIM:601419]: A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM1 is characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias, restrictive heart failure, and accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells. {ECO:0000269|PubMed:10545598, ECO:0000269|PubMed:10717012, ECO:0000269|PubMed:10905661, ECO:0000269|PubMed:11061256, ECO:0000269|PubMed:11668632, ECO:0000269|PubMed:12620971, ECO:0000269|PubMed:12766977, ECO:0000269|PubMed:14648196, ECO:0000269|PubMed:14711882, ECO:0000269|PubMed:14724127, ECO:0000269|PubMed:15495235, ECO:0000269|PubMed:15800015, ECO:0000269|PubMed:16009553, ECO:0000269|PubMed:16376610, ECO:0000269|PubMed:16865695, ECO:0000269|PubMed:17221859, ECO:0000269|PubMed:18061454, ECO:0000269|PubMed:19879535, ECO:0000269|PubMed:20829228, ECO:0000269|PubMed:22106715, ECO:0000269|PubMed:22395865, ECO:0000269|PubMed:23615443, ECO:0000269|PubMed:25394388, ECO:0000269|PubMed:27733623, ECO:0000269|PubMed:28470624, ECO:0000269|PubMed:9697706, ECO:0000269|PubMed:9736733}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations in the DES gene are associated with a variable clinical phenotype which encompasses isolated myopathies, pure cardiac phenotypes (including dilated cardiomyopathy, restrictive cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy), cardiac conduction disease, and combinations of these disorders. If both cardiologic and neurologic features occur, they can manifest in any order, as cardiologic features can precede, occur simultaneously with, or follow manifestation of generalized neuromuscular disease (PubMed:19879535). {ECO:0000269|PubMed:19879535}.; DISEASE: Cardiomyopathy, dilated 1I (CMD1I) [MIM:604765]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:10430757, ECO:0000269|PubMed:24200904, ECO:0000269|PubMed:26724190}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neurogenic scapuloperoneal syndrome Kaeser type (Kaeser syndrome) [MIM:181400]: Autosomal dominant disorder with a peculiar scapuloperoneal distribution of weakness and atrophy. A large clinical variability is observed ranging from scapuloperoneal, limb grindle and distal phenotypes with variable cardiac or respiratory involvement. Facial weakness, dysphagia and gynaecomastia are frequent additional symptoms. Affected men seemingly bear a higher risk of sudden, cardiac death as compared to affected women. Histological and immunohistochemical examination of muscle biopsy specimens reveal a wide spectrum of findings ranging from near normal or unspecific pathology to typical, myofibrillar changes with accumulation of desmin. {ECO:0000269|PubMed:17439987, ECO:0000269|PubMed:25394388}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Limb-girdle muscular dystrophy 2R (LGMD2R) [MIM:615325]: A form of limb-girdle muscular dystrophy, a disease characterized by proximal weakness, weakness of the hip and shoulder girdles and prominent asymmetrical quadriceps femoris and biceps brachii atrophy. {ECO:0000269|PubMed:23687351}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Dilated cardiomyopathy (DCM) - Homo sapiens (human);Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Arrhythmogenic Right Ventricular Cardiomyopathy;Striated Muscle Contraction;Striated Muscle Contraction;Muscle contraction;Aurora B signaling (Consensus)

Recessive Scores

• pRec: 0.122

Intolerance Scores

• loftool: 0.0939
• rvis_EVS: -0.51
• rvis_percentile_EVS: 21.56

Haploinsufficiency Scores

• pHI: 0.787
• hipred: Y
• hipred_score: 0.790
• ghis: 0.575

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.785

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Des
• Phenotype: cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: desma
• Affected structure: cardiac muscle cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: muscle contraction;cytoskeleton organization;regulation of heart contraction;muscle filament sliding;intermediate filament organization
• Cellular component: nucleus;cytosol;intermediate filament;fascia adherens;intercalated disc;Z disc;neuromuscular junction;sarcolemma;intermediate filament cytoskeleton;extracellular exosome;cardiac myofibril
• Molecular function: structural constituent of cytoskeleton;protein binding;cytoskeletal protein binding;identical protein binding