LIMS2

protein-coding

LIM zinc finger domain containing 2, the group of LIM zinc finger domain containing

Gene summary

This gene encodes a member of a small family of focal adhesion proteins which interacts with ILK (integrin-linked kinase), a protein which effects protein-protein interactions with the extraceullar matrix. The encoded protein has five LIM domains, each domain forming two zinc fingers, which permit interactions which regulate cell shape and migration. A pseudogene of this gene is located on chromosome 4. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

MANE transcript

NM_001161403.3

Inheritance

AR, AD

ClinVar variants

P:4U:183B:61

Top phenotype

Muscular dystrophy, autosomal recessive, with cardiomyopathy and triangular tongue

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr2:127,638,381-127,681,786

External References & Databases

Ensembl (ENSG00000072163)

Transcript & Mutation Effects

hg38 • Region Span ~43.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive limb-girdle muscular dystrophyNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: ClinGen

*LIMS2*, also known as *PINCH2*, was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 2015 (Chardon JW et al., PMID:25589244). Three missense variants have been reported in a pair of siblings with the limb-girdle phenotype in the literature; this is the only report known to have been published of a *LIMS2* variant identified in a patient with autosomal recessive limb-girdle muscular dystrophy. None of these variants have functional evidence in support of pathogenicity and the mechanism for disease is unknown. ClinVar contains submissions for variants within this gene; the panel contacted submitters of pathogenic and likely pathogenic ClinVar contributions and found no additional evidence to support this gene-disease relationship. The loxP/Cre system was used to knock out *LIMS2* in a mouse model. The resulting *LIMS2* deficient mice showed no apparent phenotype when compared to their wild-type and heterozygous littermates (PMID:16317048). RNA sequencing of total RNA from 20 human tissues shows non-specific expression of *LIMS2* in skeletal muscle, low to moderate in comparison to expression in other tissues (NCBI Bioproject:PRJNA280600). The evidence of this gene-disease relationship is limited to a few cases carrying missense variants and presenting with genetically heterogeneous phenotypes with a sum of genetic evidence below 0. No compelling experimental evidence is available. In summary, the evidence supporting the relationship between *LIMS2* and autosomal recessive limb-girdle muscular dystrophy has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *LIMS2* plays in this disease. This classification was approved by the ClinGen Muscular Dystrophies and Myopathies Gene Curation Expert Panel on the meeting date November 12, 2024 (SOP Version 11).

autosomal recessive limb-girdle muscular dystrophy type 2WLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014788

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive limb-girdle muscular dystrophy type 2WLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014788

Submitter: Ambry Genetics

autosomal recessive limb-girdle muscular dystrophy type 2WLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014788

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Muscular dystrophy, autosomal recessive, with cardiomyopathy and triangular tongueAD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal

Intervention: Cardiovascular

Rationale: The condition can include dilated cardiomyopathy, and knowledge may allow early diagnosis and medical management

Refs: 25589244

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LIMS2 variants in ClinVar

6 Conditions Cataloged

Autosomal recessive limb-girdle muscular dystrophy type 2WTotal: 317

not specifiedTotal: 153

not providedTotal: 37

LIMS2-related disorderTotal: 8

Decreased total neutrophil countTotal: 1

Decreased total lymphocyte countTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001161403.3. 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			3 clinvar	53 clinvar	4 clinvar	60
missense	1 clinvar		156 clinvar	4 clinvar		161
nonsense			6 clinvar			6
start loss			1 clinvar			1
frameshift		2 clinvar	5 clinvar			7
splice donor/acceptor (+/-2bp)		1 clinvar	12 clinvar			13
Total	1	3	183	57	4	248

Highest pathogenic variant AF is 0.000036563615

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 95 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001161403.3	RefSeq	NP_001154875.1	10	MANE Select
ENST00000355119.9	Ensembl	ENSP00000347240.4	10	MANE Select
NM_001136037.4	RefSeq	NP_001129509.2	11	Standard
NM_001161404.2	RefSeq	NP_001154876.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lims2	Danio rerio	Structure: pericardium Quality: edematous abnormal

Gene / Model

Organism

Observed Phenotype

lims2

Danio rerio

Structure: pericardium

Quality: edematous

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Integrin-linked kinase signaling
Cell-extracellular matrix interactions
Cell junction organization
Cell-Cell communication

Biological Process

cell junction assembly
negative regulation of apoptotic process
cell-cell junction organization
cell-cell adhesion
negative regulation of neural precursor cell proliferation

Molecular Function

metal ion binding

Cellular Component

nucleus
cytosol
plasma membrane
focal adhesion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324938
Coding exons: 10
Length: 43405
Individuals with no LoFs: 125683
Homozygous LoFs: 0
Heterozygous LoFs: 60
Defined: 125743
p: 0.000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.373	208	224	0.930	0.0000150	2387
Missense (PolyPhen)		96	95.424	1.006		963
Synonymous	1.15	81	95.2	0.850	0.00000701	664
Loss of Function	1.96	10	19.3	0.519	8.96e-7	235

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00044	0.00043	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00028	0.00027	rare
South Asian	0.00024	0.00023	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adapter protein in a cytoplasmic complex linking beta- integrins to the actin cytoskeleton, bridges the complex to cell surface receptor tyrosine kinases and growth factor receptors. Plays a role in modulating cell spreading and migration. {ECO:0000269|PubMed:12167643}.;
Disease: DISEASE: Limb-girdle muscular dystrophy 2W (LGMD2W) [MIM:616827]: A form of autosomal recessive limb-girdle muscular dystrophy, a degenerative myopathy characterized by slowly progressive wasting and weakness of the proximal muscles of arms and legs around the pelvic or shoulder girdles, elevated creatine kinase levels and dystrophic features on muscle biopsy. LGMD2W is characterized by childhood-onset of weakness progressing to a severe quadriparesis. Additionally, patients have biventricular cardiac dysfunction due to dilated cardiomyopathy. {ECO:0000269|PubMed:25589244}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.117

Intolerance Scores

LoFtool: 0.0722
RVIS EVS: -0.8
RVIS percentile EVS: 12.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.598

Gene Damage Prediction

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