GeneBe

LMOD2

protein-coding

leiomodin 2, the group of Leiomodins

Gene summary

Enables actin monomer binding activity and tropomyosin binding activity. Involved in actin nucleation; positive regulation of actin filament polymerization; and sarcomere organization. Located in M band and actin filament. Implicated in dilated cardiomyopathy 2G. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_207163.3

Inheritance

AR

ClinVar variants

P:10U:89B:20

Top phenotype

Cardiomyopathy, dilated, 2G

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr7:123,655,866-123,664,290

External References & Databases

Ensembl (ENSG00000170807)NCBI Gene (442721)OMIM (608006)HGNC:6648GenCCUniProt (Q6P5Q4)AlphaFoldClinVar (LMOD2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~8.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiomyopathy, dilated, 2GSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030887

Submitter: Ambry Genetics

cardiomyopathy, dilated, 2GSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030887

Submitter: Labcorp Genetics (formerly Invitae)

cardiomyopathy, dilated, 2GDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030887

Submitter: ClinGen

LMOD2 was evaluated for autosomal recessive dilated cardiomyopathy (DCM). LMOD2 encodes leiomodin 2, which is part of the leiomodin/tropomodulin protein family. LMOD2 is a thin filament actin-binding protein that plays a role in contraction in muscle (Tolkatchev et. al, 2022, PMID: 34273242). At the time of this review, dilated cardiomyopathy is the only condition that has been associated with this gene. At least 4 unique variants (including in-frame indel, nonsense, and intronic) have been reported in 5 human probands with DCM. Individuals typically presented with severe infant onset DCM (Yuen et. al, 2022, PMID: Lay et. al, 2022, PMID: 35188328; Sono et. al, 2023, PMID: 37296576; Ahrens-Nicklas et. al, 2019, PMID: 31517052; Greenway et. al, 2022, PMID: 34888509). One case control study was evaluated for LMOD2 (Lipov et. al, 2023, PMID: 38666070). This study also provided evidence suggesting enrichment of LMOD2 truncating variants in ICD-coded DCM in UK Biobank under a dominant model (OR = 13.7, P = 7.8e-4). However, while this information was discussed and considered in regards to the final classification of LMOD2, this evidence was unable to be scored due to privacy policies of the biobank restricting the publication of case-control values due to the small cohort. In addition, this gene-disease assertion is supported by expression studies, interaction studies, and animal models. Expression of LMOD2 in human heart tissue, as well as altered expression in patient tissues, was shown by western blot (Sono et. al, 2023, PMID: 37296576; Ahrens-Nicklas et. al, 2019, PMID: 31517052). Additionally, both a Lmod2-KO mouse model and Lmod2 piggyBac mutant mice were shown to have a DCM phenotype (Pappas et. al, 2015, PMID: 26487682; Li et. al, 2016, PMID: 27274810). Introduction of GFP-Lmod2 was also shown to rescue the DCM phenotype in Lmod2 KO mice (Pappas et. al, 2015, PMID: 26487682). Finally, an interaction between TPM1, a moderate gene for DCM, and LMOD2 was shown via NMR (Coplan et. al, 2016, PMID: 26873245). In summary, LMOD2 is definitively associated with AR DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic setting and has been upheld over time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 10/04/2024 (SOP Version 10).

dilated cardiomyopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: PanelApp Australia

cardiomyopathy, dilated, 2GDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030887

Submitter: G2P

Clinical Genomic Database (CGD)

Cardiomyopathy, dilated, 2GAR

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: The condition involves severe and early-onset dilated cardiomyopathy (which can be lethal), but awareness can allow early medical and surgical management; Heart transplant has been described

Refs: 31517052; 34888509; 35188328; 35082396Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LMOD2 variants in ClinVar

7 Conditions Cataloged
Inborn genetic diseasesTotal: 84
not specifiedTotal: 19
not providedTotal: 10
Cardiomyopathy, dilated, 2GTotal: 9
LMOD2-related conditionTotal: 8
LMOD2-related disordersTotal: 3
Familial isolated dilated cardiomyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_207163.3. 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.

EffectPLPVUSLBBSum
synonymous
11
clinvar
1
clinvar
 12
missense
88
clinvar
8
clinvar
 96
nonsense
2
clinvar
2
clinvar
 4
start loss
0
frameshift
1
clinvar
4
clinvar
1
clinvar
 6
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total4689191119

Highest pathogenic variant AF is 0.000073743206

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_207163.3RefSeqNP_997046.13MANE Select
ENST00000458573.3EnsemblENSP00000411932.23MANE Select
ENST00000456238.2EnsemblENSP00000398975.22Standard
ENST00000456238.3EnsemblENSP00000398975.22Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • muscle contraction
  • actin filament polymerization
  • myofibril assembly
  • positive regulation of actin filament polymerization
  • actin nucleation

Molecular Function

  • actin binding
  • actin monomer binding
  • tropomyosin binding

Cellular Component

  • striated muscle thin filament
  • actin filament
  • myofibril
  • sarcomere
  • M band

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000458573
Coding exons
3
Length
8484
Individuals with no LoFs
124630
Homozygous LoFs
0
Heterozygous LoFs
20
Defined
124650
p
0.0000802
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.2712822950.9560.00001583584
Missense (PolyPhen)117122.50.955071448
Synonymous0.1171151170.9860.000006951055
Loss of Function2.00816.80.4758.77e-7223

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000690.000064rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish0.000100.000099rare
East Asian0.000230.00022rare
Finnish00.0absent
European (Non-Finnish)0.000120.00012rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Mediates nucleation of actin filaments and thereby promotes actin polymerization (PubMed:18403713, PubMed:26370058, PubMed:25250574, PubMed:26417072). Plays a role in the regulation of actin filament length (By similarity). Required for normal sarcomere organization in the heart, and for normal heart function (PubMed:18403713). {ECO:0000250|UniProtKB:Q3UHZ5, ECO:0000269|PubMed:18403713, ECO:0000269|PubMed:25250574, ECO:0000269|PubMed:26370058, ECO:0000269|PubMed:26417072}.;

Intolerance Scores

LoFtool
0.399
RVIS EVS
0.15
RVIS percentile EVS
64.61

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.0879

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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