MYOT

protein-coding

myotilin, the group of I-set domain containing

Gene summary

This gene encodes a cystoskeletal protein which plays a significant role in the stability of thin filaments during muscle contraction. This protein binds F-actin, crosslinks actin filaments, and prevents latrunculin A-induced filament disassembly. Mutations in this gene have been associated with limb-girdle muscular dystrophy and myofibrillar myopathies. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[provided by RefSeq, Oct 2008]

Previous symbols:

TTID
LGMD1A
LGMD1

MANE transcript

NM_006790.3

Inheritance

ClinVar variants

P:11U:281B:130

Top phenotype

Myopathy, myofibrillar, 3

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr5:137,867,858-137,887,851

External References & Databases

Ensembl (ENSG00000120729)

Transcript & Mutation Effects

hg38 • Region Span ~20.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spheroid body myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008448

Submitter: Orphanet

myofibrillar myopathy 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012215

Submitter: PanelApp Australia

myofibrillar myopathy 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012215

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Myopathy, myofibrillar, 3AD

Manifestation: Cardiovascular; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: 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, as well as medical treatment with ACE inhibitors and/or beta-blockers); Cardiac transplantation may be necessary in individuals with severe forms of cardiomyopathy

Refs: 571956; 3275904; 9270668; 10958653; 12428213; 15111675; 16380616; 20301672; 21336781; 21676617

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYOT variants in ClinVar

21 Conditions Cataloged

Myofibrillar myopathy 3Total: 400

not providedTotal: 134

not specifiedTotal: 77

Inborn genetic diseasesTotal: 72

MYOT-related disorderTotal: 18

Heart failureTotal: 3

Foot dorsiflexor weaknessTotal: 1

EMG: myopathic abnormalitiesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006790.3. 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			6 clinvar	108 clinvar		114
missense	2 clinvar	5 clinvar	247 clinvar	20 clinvar		274
nonsense		2 clinvar	9 clinvar			11
start loss			2 clinvar			2
frameshift		1 clinvar	11 clinvar	2 clinvar		14
splice donor/acceptor (+/-2bp)		1 clinvar	6 clinvar			7
Total	2	9	281	130	0	422

Highest pathogenic variant AF is 0.000030362064

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006790.3	RefSeq	NP_006781.1	9	MANE Select
ENST00000239926.9	Ensembl	ENSP00000239926.4	9	MANE Select
NM_001135940.2	RefSeq	NP_001129412.1	7	Standard
NM_001300911.2	RefSeq	NP_001287840.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
myot	Danio rerio	Structure: skeletal muscle Quality: refractivity abnormal

Gene / Model

Organism

Observed Phenotype

myot

Danio rerio

Structure: skeletal muscle

Quality: refractivity

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

muscle contraction
homophilic cell adhesion via plasma membrane adhesion molecules
axon guidance
synapse organization

Molecular Function

actin binding
protein binding
axon guidance receptor activity
structural constituent of muscle
alpha-actinin binding

Cellular Component

plasma membrane
actin cytoskeleton
Z disc
axon
sarcolemma

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000239926
Coding exons: 9
Length: 20061
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 59
Defined: 125748
p: 0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.553	241	266	0.905	0.0000138	3249
Missense (PolyPhen)		85	98.185	0.86571		1179
Synonymous	-0.958	104	92.3	1.13	0.00000447	959
Loss of Function	1.86	16	26.3	0.609	0.00000135	310

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.00059	0.00059	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of a complex of multiple actin cross-linking proteins. Involved in the control of myofibril assembly and stability at the Z lines in muscle cells. {ECO:0000269|PubMed:12499399}.;
Disease: DISEASE: Myopathy, myofibrillar, 3 (MFM3) [MIM:609200]: 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. MFM3 is characterized by progressive skeletal muscle weakness greater distally than proximally, tight heel cords, hyporeflexia, cardiomyopathy and peripheral neuropathy in some patients. Affected muscle exhibits disorganization and streaming of the Z-line, presence of large hyaline structures, excessive accumulation of myotilin and other ectopically expressed proteins and prominent congophilic deposits. {ECO:0000269|PubMed:15111675}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spheroid body myopathy (SBM) [MIM:182920]: Autosomal dominant form of myofibrillar myopathy (MFM), characterized by slowly progressing proximal muscle weakness and dysarthric nasal speech. There is no evidence of cardiomyopathy. Muscle biopsy shows spheroid bodies within the type I muscle fibers. {ECO:0000269|PubMed:16380616}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.227

Intolerance Scores

LoFtool: 0.923
RVIS EVS: -0.31
RVIS percentile EVS: 32.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.135

Gene Damage Prediction

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