LMOD3

protein-coding

leiomodin 3, the group of Leiomodins

Gene summary

The protein encoded by this gene is a member of the leiomodin family of proteins. This protein contains three actin-binding domains, a tropomyosin domain, a leucine-rich repeat domain, and a Wiskott-Aldrich syndrome protein homology 2 domain (WH2). Localization of this protein to the pointed ends of thin filaments has been observed, and there is evidence that this protein acts as a catalyst of actin nucleation, and is important to the organization of sarcomeric thin filaments in skeletal muscles. Mutations in this gene have been associated as one cause of Nemaline myopathy, as other genes have also been linked to this disorder. Nemaline myopathy is a disorder characterized by nonprogressive generalized muscle weakness and protein inclusions (nemaline bodies) in skeletal myofibers. Patients with mutations in this gene often present with a severe congenital form of the disorder. [provided by RefSeq, Jan 2015]

MANE transcript

NM_198271.5

Inheritance

AR, AD

ClinVar variants

P:50U:215B:143

Top phenotype

Nemaline myopathy 10

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr3:69,106,065-69,123,032

External References & Databases

Ensembl (ENSG00000163380)

Transcript & Mutation Effects

hg38 • Region Span ~17.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nemaline myopathy 10DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014513

Submitter: ClinGen

The relationship between LMOD3 and Nemaline Myopathy 10 was evaluated using the ClinGen Clinical Validity Framework as of 07/31/19. Variants in LMOD3 were first reported in humans with this disease in 2014 (Yuen et al., 25250574). At least 17 variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 19 probands in 3 publications (28815944, 30291184), most of which are due to loss of function mutations leading to severe phenotypes. Although some of the probands were unable to be counted due to absent parental testing, the genetic evidence far exceeded the maximum available. Slightly more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease appears to be homozygous loss of function, as demonstrated by KO mouse models and the autosomal recessive inheritance. Summary of Experimental Data: 5.5 Points This gene-disease association is supported by two separate mouse models, each recapitulating the base phenotype of the disorder. There are several other pieces of functional evidence, most notably the interactions with KLHL40, the actin-binding function of the protein, and expression primarily in the muscle. In summary, LMOD3 is definitively associated with Nemaline Myopathy 10. Although the research is relatively recent, the amount and quality of the evidence present is more than enough to demonstrate this association. This classification was approved by the ClinGen Aminoacidopathy Working Group on 09/09/2019.

typical nemaline myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015737

Submitter: Orphanet

nemaline myopathy 10DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014513

Submitter: G2P

nemaline myopathy 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014513

Submitter: Labcorp Genetics (formerly Invitae)

nemaline myopathy 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014513

Submitter: PanelApp Australia

severe congenital nemaline myopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015735

Submitter: Orphanet

Clinical Genomic Database (CGD)

Nemaline myopathy 10AR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25250574; 30291184

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LMOD3 variants in ClinVar

6 Conditions Cataloged

Nemaline myopathy 10Total: 398

Inborn genetic diseasesTotal: 78

not providedTotal: 76

not specifiedTotal: 22

LMOD3-related disorderTotal: 19

Joubert syndrome 24Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198271.5. 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				116 clinvar	2 clinvar	118
missense	2 clinvar	4 clinvar	213 clinvar	21 clinvar	4 clinvar	244
nonsense	15 clinvar	3 clinvar				18
start loss						0
frameshift	22 clinvar	4 clinvar	1 clinvar			27
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	39	11	215	137	6	408

Highest pathogenic variant AF is 0.000027365433

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_198271.5	RefSeq	NP_938012.2	3	MANE Select
ENST00000420581.7	Ensembl	ENSP00000414670.3	3	MANE Select
NM_001304418.3	RefSeq	NP_001291347.1	3	Standard
ENST00000475434.1	Ensembl	ENSP00000418645.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lmod3	Danio rerio	Structure: muscle cell Quality: increased distance abnormal

Gene / Model

Organism

Observed Phenotype

lmod3

Danio rerio

Structure: muscle cell

Quality: increased distance

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

muscle contraction
striated muscle contraction
myofibril assembly
skeletal muscle thin filament assembly
actin nucleation

Molecular Function

actin monomer binding
tropomyosin binding

Cellular Component

cytoplasm
striated muscle thin filament
myofibril
M band

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000420581
Coding exons: 3
Length: 16161
Individuals with no LoFs: 124575
Homozygous LoFs: 0
Heterozygous LoFs: 72
Defined: 124647
p: 0.000289

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.618	331	301	1.10	0.0000162	3761
Missense (PolyPhen)		132	126.93	1.0399		1587
Synonymous	-1.30	133	115	1.15	0.00000673	988
Loss of Function	1.12	13	18.2	0.716	9.42e-7	248

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00026	rare
Latino/Admixed American	0.00053	0.00052	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00017	rare
Finnish	0.000052	0.000046	rare
European (Non-Finnish)	0.00017	0.00016	rare
South Asian	0.00079	0.00078	rare
Other	0.00067	0.00066	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Essential for the organization of sarcomeric actin thin filaments in skeletal muscle (PubMed:25250574). Increases the rate of actin polymerization (PubMed:25250574). {ECO:0000269|PubMed:25250574}.;
Disease: DISEASE: Nemaline myopathy 10 (NEM10) [MIM:616165]: An autosomal recessive severe form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. NEM10 is characterized by early-onset generalized muscle weakness and hypotonia with respiratory insufficiency and feeding difficulties. Additional features include arthrogryposis or congenital contractures, ophthalmoplegia, a history of prematurity, reduced fetal movements, and polyhydramnios. Most patients die of respiratory failure in early infancy. {ECO:0000269|PubMed:25250574}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: 2.29
RVIS percentile EVS: 98.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.209

Gene Damage Prediction

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